研究者基本情報

• 博士（医学）, 北海道大学

• https://researchmap.jp/manabu_igarashi

• https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201301011296456953
• http://kaken.nii.ac.jp/d/r/10374240.ja.html

• 10374240

• 201301011296456953

• 抗ウイルス薬
• 分子モデリング
• フィロウイルス
• 分子動力学
• 蛋白質
• 分子シミュレーション
• 生体生命情報学
• 人獣共通感染症
• 薬剤耐性
• ウイルス
• インフルエンザ
• インシリコ創薬
• 計算科学

• ライフサイエンス, 獣医学

• 博士課程, 国際感染症学院

研究活動情報

• Length and density of α2-3 sialyllactose-containing chains on glycopolymers determine receptor binding of avian influenza viruses
  Daiki Kobayashi; Takahiro Hiono; Ryota Adachi; Manabu Igarashi; Takahiko Matsushita; Norikazu Isoda; Yoshihiro Sakoda; Koji Matsuoka
  Archives of Virology, 171, 3, Springer Science and Business Media LLC, 2026年02月26日
  研究論文（学術雑誌）
• Discovery of potent cross-neutralizing antibodies against Marburg and Ravn viruses with therapeutic potential.
  Takeshi Saito; Hiroko Miyamoto; Manabu Igarashi; Asuka Nanbo; Risa Hayashi; Ruchi Paroha; Gavriella Siman-Tov; Kirsten Littlefield; Akina Mori-Kajihara; Christine Click; Wakako Furuyama; Slobodan Paessler; Junki Maruyama; Ayato Takada
  Npj viruses, 3, 1, 84, 84, 2025年12月27日, ［国際誌］
  英語, 研究論文（学術雑誌）, Marburg virus (MARV) and Ravn virus (RAVV) are highly pathogenic filoviruses that cause Marburg virus disease (MVD), for which no approved treatment currently exists. In this study, we describe a panel of 10 novel mouse-derived monoclonal antibodies (mAbs), all exhibiting neutralizing activity against MARV. Notably, five of these mAbs also cross-neutralize RAVV. Based on amino acid sequences, neutralization profiles, and escape mutations in the MARV glycoprotein (GP), the mAbs were classified into three groups. mAbs targeting the receptor-binding domain (RBD) and mucin-like domain exhibited MARV-specific neutralization, whereas those targeting epitopes spanning the RBD and internal fusion loop exhibited cross-neutralization. Post-exposure administration of cross-neutralizing mAbs (AGP-R7, AGP-R12) provided significant protection in MARV and RAVV infection mouse models. These findings identify a conserved neutralizing epitope with therapeutic potential and highlight AGP-R7 and AGP-R12 as promising candidates for MVD treatment. This study offers new insights into cross-reactive antibody strategies against multiple filoviruses.
• Molecular and Functional Characterization of Sika Deer ACE2 as a Receptor for SARS-CoV-2.
  Anastasiia Kovba; Manabu Igarashi; Keita Mizuma; Yuma Ohari; Manabu Onuma; Michito Shimozuru; Kotaro Shimizu; Masami Yamanaka; Keita Matsuno; Toshio Tsubota
  Microbiology and immunology, 2025年09月30日, ［国際誌］
  英語, 研究論文（学術雑誌）, Surveillance of SARS-CoV-2 in white-tailed deer (WTD, Odocoileus virginianus) has revealed its widespread and sustained transmission across North America, with evidence suggesting possible transmission from deer to humans. In the following surveillance studies in other deer species, however, little evidence of infection spread was found, including in sika deer (Cervus nippon) in our previous study. Differences in the structure of the virus entry receptor angiotensin-converting enzyme 2 (ACE2) are known to act as one of the functional barriers to SARS-CoV-2 infection. To investigate the molecular basis of the lack of SARS-CoV-2 transmission to sika deer, we performed structural and functional analyses of the sika deer ACE2 in comparison with WTD ACE2. Comparison of sika deer ACE2 sequence and those of cervid species with WTD ACE2, followed by in silico molecular dynamics analysis, revealed a substitution of lysine to asparagine in position 31 commonly found in cervid ACE2s can potentially alter binding to the SARS-CoV-2 spike (S) protein receptor-binding domain (RBD). Functional assays in cells expressing sika deer and WTD ACE2s showed minimal differences in viral binding and replication, demonstrating that SARS-CoV-2 can similarly utilize ACE2 from both species. These findings suggest that sika deer and possibly other cervids may be highly susceptible to SARS-CoV-2 and highlight the need to investigate other factors impacting virus spread in deer populations.
• Comparison of the biological properties of bat-derived filovirus envelope glycoproteins.
  Francois Edidi-Atani; Yannick Munyeku Bazitama; Hiroko Miyamoto; Akina Mori-Kajihara; Hayato Sugiura; Manabu Igarashi; Jean Jacques Muyembe-Tamfum; Steve Ahuka-Mundeke; Ayato Takada
  Journal of virology, e0101825, 2025年09月25日, ［国際誌］
  英語, 研究論文（学術雑誌）, Although some filoviruses, such as Ebola virus (EBOV) and Marburg virus (MARV), are highly pathogenic in humans, novel filoviruses, including Lloviu virus (LLOV), Bombali virus (BOMV), Mengla virus (MLAV), and Dehong virus (DEHV), whose biological properties are poorly understood, have been found in bats. In this study, we characterized the envelope glycoproteins (GPs) of these bat-derived filoviruses (BatFiloVs). We first confirmed that virus-like particles consisting of their GPs, nucleoproteins, and matrix proteins were filamentous. Interestingly, although BatFiloVs were serologically distinct, some previously established monoclonal antibodies (MAbs) (e.g., 6D6) successfully neutralized vesicular stomatitis Indiana viruses pseudotyped with LLOV, BOMV, or DEHV GPs. The pseudotyped viruses bearing BatFiloV GPs utilized human TIM-1 and C-type lectins for entry into cells, although the efficiency tended to be lower than for EBOV and/or MARV GP-pseudotyped viruses. These viruses broadly infected cultured cells derived from various animal species, including humans and bats. However, viruses pseudotyped with DEHV and MARV GPs failed to infect the Yaeyama flying fox cell line, whereas the other pseudotyped viruses infected this cell line. Interestingly, the virus bearing BOMV GP showed the greatest ability to infect cell lines derived from Angolan free-tailed bats, the only known host species of BOMV. We identified unique amino acid residues at the interface between GP and its receptor (i.e., Niemann-Pick C1), which might explain these differences. Our results suggest that the biological properties of filovirus GPs are generally consistent with their phylogenetic relationship and that BatFiloVs may have differential pathogenicity and host range restriction.IMPORTANCEFiloviruses, such as EBOV and MARV, are known to cause severe hemorrhagic fever in humans and nonhuman primates. With the recent advancements in next-generation sequencing, novel filoviruses have been detected in bats. However, their pathogenicity and host tropism remain largely unknown. Here, we focus on the filovirus spike protein GP, which plays a crucial role in the viral lifecycle, and discuss the biological properties of BatFiloVs. We studied the primary structures of GPs, virus particle morphology, antigenic differences of GPs, neutralizing capacities of anti-EBOV and -MARV GP MAbs, usage of some attachment factors during the entry into cells, and GP-mediated cellular tropism. The present study provides fundamental information for understanding the BatFiloV ecology, host ranges, and potential risks as zoonotic pathogens for humans. This knowledge will guide public health interventions to prevent virus spillovers and the development of surveillance strategies and specific countermeasures.
• Exploring suramin's antiviral effects: targeting Lymphocytic Choriomeningitis virus cell entry and replication/transcription processes.
  Shuzo Urata; Tomoko Tsuruta; Manabu Igarashi
  Virology, 609, 110557, 110557, 2025年08月, ［国際誌］
  英語, 研究論文（学術雑誌）, The Arenavirus family comprises of multiple pathogenic human viruses. Currently, there are no licensed vaccines or antiviral agents against arenavirus infections; therefore, there is a pressing need to develop prophylaxis and/or countermeasures. Suramin is an approved antiparasitic drug that also blocks the propagation of multiple viruses. In this study, the antiviral effect of suramin against lymphocytic choriomeningitis virus (LCMV), a prototype of the arenavirus, was examined. Our results showed that suramin targeted at least two replication steps of LCMV, an entry step and a replication step, but not the particle production step. Our in silico study revealed that the target of suramin in replication could be an RNA-dependent RNA polymerase (L), and this observation was consistent with previous reports from other viral families, including coronaviruses and filoviruses. These results imply that suramin has less potential to emerge as a suramin-resistant LCMV due to its dual viral targets.
• A cap-dependent endonuclease inhibitor acts as a potent antiviral agent against La Crosse virus infection.
  Kei Konishi; Yoshiyuki Taoda; Manabu Igarashi; Takao Shishido; Kazuya Yasuo; William W Hall; Yasuko Orba; Hirofumi Sawa; Michihito Sasaki; Akihiko Sato
  Antimicrobial agents and chemotherapy, e0018625, 2025年07月23日, ［国際誌］
  英語, 研究論文（学術雑誌）, La Crosse virus (LACV) infection, the causative agent of La Crosse encephalitis, can lead to severe neurological symptoms and sequelae, particularly in children. Despite annual reports of neurologically symptomatic cases, no effective treatment has yet been established. Bunyaviruses, including LACV, utilize a cap-snatching mechanism for transcription, with a cap-dependent endonuclease (CEN) serving as a promising target for antiviral treatment. Specifically, we now demonstrate that a CEN inhibitor, carbamoyl pyridone carboxylic acid (CAPCA)-1, exhibits potent anti-LACV activity in vitro and in vivo. CAPCA-1 exhibited 50% effective concentration values below 1 µM in neuronal and non-neuronal cells, demonstrating a higher in vitro activity than the nucleoside analogs, ribavirin and favipiravir. Multiple passages of LACV in the presence of CAPCA-1 produced numerous amino acid mutations in the CEN active site. Notably, using a lethal infection model in mice, CAPCA-1 treatment reduced viral loads in the brain and extended the survival rate of LACV-infected mice. These findings highlight the potential of CEN inhibitors as treatment options for La Crosse encephalitis.
• Herpes simplex virus 1 evades APOBEC1-mediated immunity via its uracil-DNA glycosylase in mice.
  Akihisa Kato; Hayato Harima; Yuji Tsunekawa; Manabu Igarashi; Kouichi Kitamura; Kousho Wakae; Tomoaki Nishiyama; Satoru Morimoto; Toru Suzuki; Hiroko Kozuka-Hata; Masaaki Oyama; Daisuke Motooka; Mizuki Watanabe; Kousuke Takeshima; Yuhei Maruzuru; Naoto Koyanagi; Hideyuki Okano; Toshifumi Inada; Takashi Okada; Masamichi Muramatsu; Yasushi Kawaguchi
  Nature microbiology, 2025年06月03日, ［国際誌］
  英語, 研究論文（学術雑誌）, Herpes simplex virus 1 (HSV-1) is the most common cause of viral encephalitis, which can be lethal or result in severe neurological defects despite antiviral therapy. The apolipoprotein B messenger-RNA editing enzyme, catalytic polypeptide-like (APOBEC) group of proteins can act as viral restriction factors. How HSV-1 evades this intrinsic immune mechanism is unclear. Here, using human carcinoma HEp-2 cells, we find that phosphorylation and therefore activation of HSV-1 uracil-DNA glycosylase counteracts mouse APOBEC1 DNA-editing activity on HSV-1 genomes. This protects viral genomes, promotes viral replication and encephalitis in the central nervous system of mice. Presence of Apobec1 improved encephalitis outcomes in mice challenged with HSV-1 carrying a mutation in the phosphorylation site of uracil-DNA glycosylase. Treatment with an UNG inhibitor, adeno-associated virus vector expressing UGI, protected wild-type HSV-1-infected mice from lethal encephalitis. These findings identify uracil-DNA glycosylase as a viral factor enabling evasion from intrinsic antiviral immunity mediated by APOBEC1 in the central nervous system and suggests a potential therapeutic approach to treat HSV-1 encephalitis.
• Functional dissection of the C-terminal domain of rabies virus RNA polymerase L protein.
  Fumiki Izumi; Machiko Makino; Michihito Sasaki; Kento Nakagawa; Tatsuki Takahashi; Shoko Nishiyama; Yuji Fujii; Misuzu Okajima; Tatsunori Masatani; Manabu Igarashi; Hirofumi Sawa; Makoto Sugiyama; Naoto Ito
  Journal of virology, e0208224, 2025年03月11日, ［国際誌］
  英語, 研究論文（学術雑誌）, UNLABELLED: The rabies virus large (L) protein interacts with its cofactor phosphoprotein (P protein) to function as an RNA-dependent RNA polymerase (RdRp). The C-terminal domain (CTD) of the L protein plays a critical role in P protein binding. We previously reported that the highly conserved NPYNE sequence in the hydrophilic region of the CTD (positions 1929-1933 of the L protein [L1929-1933]) is important for both P protein binding and RdRp function. To elucidate the functional role of the CTD in detail, we examined the importance of each of the hydrophilic residues in the NPYNE sequence (underlined). A rabies virus mutant with Ala substitutions in these hydrophilic residues showed low replication capacity. Comprehensive analyses of a revertant of the mutant virus and a series of L protein mutants revealed that Asn at L1929 is crucial for both P protein binding and RdRp function. Analyses of the L protein mutants also showed that Asn at L1932 and Glu at L1933 have roles in RdRp function and P protein binding, respectively. Furthermore, we demonstrated that the NPYNE sequence is essential for stabilizing the L protein through the L-P interaction. In a previously determined L protein structure, all of the hydrophilic residues in the NPYNE sequence form the first α-helix in the CTD. Therefore, our findings indicate that this helix is important for P protein-binding ability, RdRp function, and stabilization of the L protein, thereby contributing to efficient viral replication. IMPORTANCE: Although RNA-dependent RNA polymerase of rhabdoviruses, which is composed of the large (L) protein and its cofactor phosphoprotein (P protein), has a high potential as a target for therapeutics against the viruses, the relationship between the structure and molecular functions is poorly understood. In this study, we functionally examined the C-terminal domain (CTD) of the rabies virus L protein as a model for the rhabdovirus L protein. We showed that the first α-helix in the CTD is important for the P protein-binding ability, RdRp function, and stability of the L protein. Since in the L-P complex structure, this helix does not form an interface with the P protein, we provide here the first evidence of an indirect contribution of the L protein CTD to the L-P interaction in rhabdoviruses. The findings in this study will be useful for developing therapeutics targeting the L-P interaction.
• Altered receptor-binding specificity of gull-adapted H13 avian influenza viruses corresponds to their unique host preferences.
  Rio Harada; Takahiro Hiono; Manabu Igarashi; Daiki Kobayashi; Hinako Ban; Norikazu Isoda; Yoshihiro Sakoda
  Virology, 605, 110460, 110460, 2025年02月21日, ［国際誌］
  英語, 研究論文（学術雑誌）, Avian influenza viruses (AIVs) recognize α2-3 sialosides as receptors. Previous studies showed that the structural diversity within α2-3 sialosides is related to the host specificity of AIVs. H13 AIVs are primarily isolated from gulls, although almost all AIV subtypes have been isolated from ducks, the natural hosts of AIVs. To elucidate the molecular basis of the host specificity of H13 viruses to gulls, the receptor-binding specificity of H13 hemagglutinins (HAs) and the distribution of viral receptors in gulls were investigated. The results revealed that recombinant HA (rHA) of H13 viruses had a binding preference for fucosylated α2-3 sialosides, which were distributed widely in the respiratory tract and intestines of gulls but not in the colon of ducks. Moreover, the receptor-binding specificity of mutant rHAs revealed that amino acids in the 130-loop and at position 227 of H13 HA were critical for the preference for fucosylated α2-3 sialosides. The results of the present study suggest that the binding specificity of H13 HA to fucosylated α2-3 sialosides is a key factor for the host susceptibility of H13 viruses to gulls.
• Identification of an ambisense kolmiovirus from birds
  Mai Kishimoto; Sakiho Imai; Manabu Igarashi; Masayuki Horie
  2025年01月08日
• Stability of Bas-Congo virus neutralising antibodies in serum samples during long-term storage-Authors' reply.
  Yannick Munyeku-Bazitama; Patient Okitale-Talunda; Takanari Hattori; Takeshi Saito; Boniface Pongombo Lombe; Hiroko Miyamoto; Akina Mori-Kajihara; Masahiro Kajihara; Agathe Bikupe Nkoy; Augustin Tshibwabwa Twabela; Justin Masumu; Steve Ahuka-Mundeke; Jean-Jacques Muyembe-Tamfum; Manabu Igarashi; Eun-Sil Park; Shigeru Morikawa; Sheila Makiala-Mandanda; Ayato Takada
  The Lancet. Microbe, 5, 10, 100917, 100917, 2024年10月, ［国際誌］
  英語
• Hexestrol, an estrogen receptor agonist, inhibits Lassa virus entry.
  Zihan Zhang; Toru Takenaga; Sarah Katharina Fehling; Manabu Igarashi; Takatsugu Hirokawa; Yukiko Muramoto; Koji Yamauchi; Chiho Onishi; Masahiro Nakano; Shuzo Urata; Allison Groseth; Thomas Strecker; Takeshi Noda
  Journal of virology, 98, 7, e0071424, 2024年07月23日, ［国際誌］
  英語, 研究論文（学術雑誌）, Lassa virus (LASV) is the causative agent of human Lassa fever which in severe cases manifests as hemorrhagic fever leading to thousands of deaths annually. However, no approved vaccines or antiviral drugs are currently available. Recently, we screened approximately 2,500 compounds using a recombinant vesicular stomatitis virus (VSV) expressing LASV glycoprotein GP (VSV-LASVGP) and identified a P-glycoprotein inhibitor as a potential LASV entry inhibitor. Here, we show that another identified candidate, hexestrol (HES), an estrogen receptor agonist, is also a LASV entry inhibitor. HES inhibited VSV-LASVGP replication with a 50% inhibitory concentration (IC50) of 0.63 µM. Importantly, HES also inhibited authentic LASV replication with IC50 values of 0.31 µM-0.61 µM. Time-of-addition and cell-based membrane fusion assays suggested that HES inhibits the membrane fusion step during virus entry. Alternative estrogen receptor agonists did not inhibit VSV-LASVGP replication, suggesting that the estrogen receptor itself is unlikely to be involved in the antiviral activity of HES. Generation of a HES-resistant mutant revealed that the phenylalanine at amino acid position 446 (F446) of LASVGP, which is located in the transmembrane region, conferred resistance to HES. Although mutation of F446 enhanced the membrane fusion activity of LASVGP, it exhibited reduced VSV-LASVGP replication, most likely due to the instability of the pre-fusion state of LASVGP. Collectively, our results demonstrated that HES is a promising anti-LASV drug that acts by inhibiting the membrane fusion step of LASV entry. This study also highlights the importance of the LASVGP transmembrane region as a target for anti-LASV drugs.IMPORTANCELassa virus (LASV), the causative agent of Lassa fever, is the most devastating mammarenavirus with respect to its impact on public health in West Africa. However, no approved antiviral drugs or vaccines are currently available. Here, we identified hexestrol (HES), an estrogen receptor agonist, as the potential antiviral candidate drug. We showed that the estrogen receptor itself is not involved in the antiviral activity. HES directly bound to LASVGP and blocked membrane fusion, thereby inhibiting LASV infection. Through the generation of a HES-resistant virus, we found that phenylalanine at position 446 (F446) within the LASVGP transmembrane region plays a crucial role in the antiviral activity of HES. The mutation at F446 caused reduced virus replication, likely due to the instability of the pre-fusion state of LASVGP. These findings highlight the potential of HES as a promising candidate for the development of antiviral compounds targeting LASV.
• Characterization of human tibrovirus envelope glycoproteins
  Yannick Munyeku-Bazitama; Takeshi Saito; Takanari Hattori; Hiroko Miyamoto; Boniface Pongombo Lombe; Akina Mori-Kajihara; Masahiro Kajihara; Jean-Jacques Muyembe-Tamfum; Manabu Igarashi; Eun-sil Park; Shigeru Morikawa; Sheila Makiala-Mandanda; Ayato Takada
  Journal of Virology, American Society for Microbiology, 2024年07月02日
  研究論文（学術雑誌）, ABSTRACT
  
  Tibroviruses are novel rhabdoviruses detected in humans, cattle, and arthropods. Four tibroviruses are known to infect humans: Bas-Congo virus (BASV), Ekpoma virus 1 (EKV-1), Ekpoma virus 2, and Mundri virus. However, since none of them has been isolated, their biological properties are largely unknown. We aimed to characterize the human tibrovirus glycoprotein (G), which likely plays a pivotal role in viral tropism and pathogenicity. Human tibrovirus Gs were found to share some primary structures and display 14 conserved cysteine residues, although their overall amino acid homology was low (29%–48%). Multiple potential glycosylation sites were found on the G molecules, and endoglycosidase H- and peptide-N-glycosidase F-sensitive glycosylation was confirmed. AlphaFold-predicted three-dimensional (3D) structures of human tibrovirus Gs were overall similar. Membrane fusion mediated by these tibrovirus Gs was induced by acidic pH. The low pH-induced conformational change that triggers fusion was reversible. Virus-like particles (VLPs) were produced by transient expression of Gs in cultured cells and used to produce mouse antisera. Using vesicular stomatitis Indiana virus pseudotyped with Gs, we found that the antisera to the respective tibrovirus VLPs showed limited cross-neutralizing activity. It was also found that human C-type lectins and T-cell immunoglobulin mucin 1 acted as attachment factors for G-mediated entry into cells. Interestingly, BASV-G showed the highest ability to utilize these molecules. The viruses infected a wide range of cell lines with preferential tropism for human-derived cells whereas the preference of EKV-1 was unique compared with the other human tibroviruses. These findings provide fundamental information to understand the biological properties of the human tibroviruses.
  
  IMPORTANCE
  
  Human tibroviruses are poorly characterized emerging rhabdoviruses associated with either asymptomatic infection or severe disease with a case fatality rate as high as 60% in humans. However, the extent and burden of human infection as well as factors behind differences in infection outcomes are largely unknown. In this study, we characterized human tibrovirus glycoproteins, which play a key role in virus-host interactions, mainly focusing on their structural and antigenic differences and cellular tropism. Our results provide critical information for understanding the biological properties of these novel viruses and for developing appropriate preparedness interventions such as diagnostic tools, vaccines, and effective therapies.
• Seroprevalence of Bas-Congo virus in Mangala, Democratic Republic of the Congo: a population-based cross-sectional study
  Yannick Munyeku-Bazitama; Patient Okitale-Talunda; Takanari Hattori; Takeshi Saito; Boniface Pongombo Lombe; Hiroko Miyamoto; Akina Mori-Kajihara; Masahiro Kajihara; Agathe Bikupe Nkoy; Augustin Tshibwabwa Twabela; Justin Masumu; Steve Ahuka-Mundeke; Jean-Jacques Muyembe-Tamfum; Manabu Igarashi; Eun-sil Park; Shigeru Morikawa; Sheila Makiala-Mandanda; Ayato Takada
  The Lancet Microbe, Elsevier BV, 2024年03月
  研究論文（学術雑誌）
• Targeting cap1 RNA methyltransferases as an antiviral strategy.
  Yuta Tsukamoto; Manabu Igarashi; Hiroki Kato
  Cell chemical biology, 2023年12月05日, ［国際誌］
  英語, 研究論文（学術雑誌）, Methylation is one of the critical modifications that regulates numerous biological processes. Guanine capping and methylation at the 7th position (m7G) have been shown to mature mRNA for increased RNA stability and translational efficiency. The m7G capped cap0 RNA remains immature and requires additional methylation at the first nucleotide (N1-2'-O-Me), designated as cap1, to achieve full maturation. This cap1 RNA with N1-2'-O-Me prevents its recognition by innate immune sensors as non-self. Viruses have also evolved various strategies to produce self-like capped RNAs with the N1-2'-O-Me that potentially evades the antiviral response and establishes an efficient replication. In this review, we focus on the importance of the presence of N1-2'-O-Me in viral RNAs and discuss the potential for drug development by targeting host and viral N1-2'-O-methyltransferases.
• Development of flavivirus subviral particles with low cross-reactivity by mutations of a distinct antigenic domain
  Koshiro Tabata; Yukari Itakura; Takuma Ariizumi; Manabu Igarashi; Hiroko Kobayashi; Kittiya Intaruck; Mai Kishimoto; Shintaro Kobayashi; William W. Hall; Michihito Sasaki; Hirofumi Sawa; Yasuko Orba
  Applied Microbiology and Biotechnology, 107, 24, 7515, 7529, Springer Science and Business Media LLC, 2023年10月13日
  研究論文（学術雑誌）, Abstract
  
  The most conserved fusion loop (FL) domain present in the flavivirus envelope protein has been reported as a dominant epitope for cross-reactive antibodies to mosquito-borne flaviviruses (MBFVs). As a result, establishing accurate serodiagnosis for MBFV infections has been difficult as anti-FL antibodies are induced by both natural infection and following vaccination. In this study, we modified the most conserved FL domain to overcome this cross-reactivity. We showed that the FL domain of lineage I insect-specific flavivirus (ISFV) has differences in antigenicity from those of MBFVs and lineage II ISFV and determined the key amino acid residues (G106, L107, or F108), which contribute to the antigenic difference. These mutations were subsequently introduced into subviral particles (SVPs) of dengue virus type 2 (DENV2), Zika virus (ZIKV), Japanese encephalitis virus (JEV), and West Nile virus (WNV). In indirect enzyme-linked immunosorbent assays (ELISAs), these SVP mutants when used as antigens reduced the binding of cross-reactive IgG and total Ig induced by infection of ZIKV, JEV, and WNV in mice and enabled the sensitive detection of virus-specific antibodies. Furthermore, immunization of ZIKV or JEV SVP mutants provoked the production of antibodies with lower cross-reactivity to heterologous MBFV antigens compared to immunization with the wild-type SVPs in mice. This study highlights the effectiveness of introducing mutations in the FL domain in MBFV SVPs with lineage I ISFV-derived amino acids to produce SVP antigens with low cross-reactivity and demonstrates an improvement in the accuracy of indirect ELISA-based serodiagnosis for MBFV infections.
  
  Key points
  
  • The FL domain of Lineage I ISFV has a different antigenicity from that of MBFVs.• Mutated SVPs reduce the binding of cross-reactive antibodies in indirect ELISAs.• Inoculation of mutated SVPs induces antibodies with low cross-reactivity.
• Evasion of APOBEC1-mediated Intrinsic Immunity by a Herpesvirus Uracil DNA Glycosylase Is a Determinant of Viral Encephalitis
  Akihisa Kato; Hayato Harima; Yuji Tsunekawa; Manabu Igarashi; Kouichi Kitamura; Kousho Wakae; Hiroko Kozuka-Hata; Masaaki Oyama; Mizuki Watanabe; Kousuke Takeshima; Yuhei Maruzuru; Naoto Koyanagi; Takashi Okada; Masamichi Muramatsu; Yasushi Kawaguchi
  Cold Spring Harbor Laboratory, 2023年06月23日
  研究論文（学術雑誌）, Herpes simplex virus 1 (HSV-1) is the most common cause of viral encephalitis, which can be lethal or result in severe neurological defects, even when treated with antiviral therapy. We demonstrated that activation of HSV-1 uracil-DNA glycosylase (vUNG) by phosphorylation, essential for its enzymatic activity, counteracted APOBEC1 to promote viral replication and encephalitis in the central nervous system (CNS) of mice. The activation of vUNG protected HSV-1 genomes from APOBEC1-mediated DNA editing, allowing efficient viral replication to occur. The presence of APOBEC1 markedly improved lethal encephalitis in mice infected with an HSV-1 mutant carrying a mutation in the phosphorylation site and an UNG inhibitor protected wild-type HSV-1-infected mice from lethal encephalitis. These findings re-define vUNG as an important factor that allows evasion from intrinsic anti-viral immunity mediated by APOBEC1 in the CNS, and suggest a new therapeutic approach for the treatment of fetal and critical HSV-1 encephalitis.
• Structural and Energetic Basis for Differential Binding of Ebola and Marburg Virus Glycoproteins to a Bat-Derived Niemann-Pick C1 Protein
  Manabu Igarashi; Takatsugu Hirokawa; Ayato Takada
  The Journal of Infectious Diseases, 228, Supplement_7, S479, S487, Oxford University Press (OUP), 2023年04月29日
  研究論文（学術雑誌）, Abstract
  
  Background
  
  Our previous study demonstrated that the fruit bat (Yaeyama flying fox)-derived cell line FBKT1 showed preferential susceptibility to Ebola virus (EBOV), whereas the human cell line HEK293T was similarly susceptible to EBOV and Marburg virus (MARV). This was due to 3 amino acid differences of the endosomal receptor Niemann-Pick C1 (NPC1) between FBKT1 and HEK293T (ie, TET and SGA, respectively, at positions 425–427), as well as 2 amino acid differences at positions 87 and 142 of the viral glycoprotein (GP) between EBOV and MARV.
  
  Methods/Results
  
  To understand the contribution of these amino acid differences to interactions between NPC1 and GP, we performed molecular dynamics simulations and binding free energy calculations. The average binding free energies of human NPC1 (hNPC1) and its mutant having TET at positions 425–427 (hNPC1/TET) were similar for the interaction with EBOV GP. In contrast, hNPC1/TET had a weaker interaction with MARV GP than wild-type hNPC1. As expected, substitutions of amino acid residues at 87 or 142 in EBOV and MARV GPs converted the binding affinity to hNPC1/TET.
  
  Conclusions
  
  Our data provide structural and energetic insights for understanding potential differences in the GP-NPC1 interaction, which could influence the host tropism of EBOV and MARV.
• Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication.
  Yuta Tsukamoto; Takahiro Hiono; Shintaro Yamada; Keita Matsuno; Aileen Faist; Tobias Claff; Jianyu Hou; Vigneshwaran Namasivayam; Anja Vom Hemdt; Satoko Sugimoto; Jin Ying Ng; Maria H Christensen; Yonas M Tesfamariam; Steven Wolter; Stefan Juranek; Thomas Zillinger; Stefan Bauer; Takatsugu Hirokawa; Florian I Schmidt; Georg Kochs; Masayuki Shimojima; Yi-Shuian Huang; Andreas Pichlmair; Beate M Kümmerer; Yoshihiro Sakoda; Martin Schlee; Linda Brunotte; Christa E Müller; Manabu Igarashi; Hiroki Kato
  Science (New York, N.Y.), 379, 6632, 586, 591, 2023年02月10日, ［国際誌］
  英語, 研究論文（学術雑誌）, Orthomyxo- and bunyaviruses steal the 5' cap portion of host RNAs to prime their own transcription in a process called "cap snatching." We report that RNA modification of the cap portion by host 2'-O-ribose methyltransferase 1 (MTr1) is essential for the initiation of influenza A and B virus replication, but not for other cap-snatching viruses. We identified with in silico compound screening and functional analysis a derivative of a natural product from Streptomyces, called trifluoromethyl-tubercidin (TFMT), that inhibits MTr1 through interaction at its S-adenosyl-l-methionine binding pocket to restrict influenza virus replication. Mechanistically, TFMT impairs the association of host cap RNAs with the viral polymerase basic protein 2 subunit in human lung explants and in vivo in mice. TFMT acts synergistically with approved anti-influenza drugs.
• Single Nucleotide Variants of the Human TIM-1 IgV Domain with Reduced Ability to Promote Viral Entry into Cells
  Takanari Hattori; Takeshi Saito; Hiroko Miyamoto; Masahiro Kajihara; Manabu Igarashi; Ayato Takada
  Viruses, 14, 10, 2124, 2124, MDPI AG, 2022年09月26日
  研究論文（学術雑誌）, Human T-cell immunoglobulin mucin 1 (hTIM-1) is known to promote cellular entry of enveloped viruses. Previous studies suggested that the polymorphisms of hTIM-1 affected its function. Here, we analyzed single nucleotide variants (SNVs) of hTIM-1 to determine their ability to promote cellular entry of viruses using pseudotyped vesicular stomatitis Indiana virus (VSIV). We obtained hTIM-1 sequences from a public database (Ensembl genome browser) and identified 35 missense SNVs in 3 loops of the hTIM-1 immunoglobulin variable (IgV) domain, which had been reported to interact with the Ebola virus glycoprotein (GP) and phosphatidylserine (PS) in the viral envelope. HEK293T cells transiently expressing wildtype hTIM-1 or its SNV mutants were infected with VSIVs pseudotyped with filovirus or arenavirus GPs, and their infectivities were compared. Eleven of the thirty-five SNV substitutions reduced the efficiency of hTIM-1-mediated entry of pseudotyped VSIVs. These SNV substitutions were found not only around the PS-binding pocket but also in other regions of the molecule. Taken together, our findings suggest that some SNVs of the hTIM-1 IgV domain have impaired ability to interact with PS and/or viral GPs in the viral envelope, which may affect the hTIM-1 function to promote viral entry into cells.
• Attenuation of SARS-CoV-2 replication and associated inflammation by concomitant targeting of viral and host cap 2'-O-ribose methyltransferases.
  Valter Bergant; Shintaro Yamada; Vincent Grass; Yuta Tsukamoto; Teresa Lavacca; Karsten Krey; Maria-Teresa Mühlhofer; Sabine Wittmann; Armin Ensser; Alexandra Herrmann; Anja Vom Hemdt; Yuriko Tomita; Shutoku Matsuyama; Takatsugu Hirokawa; Yiqi Huang; Antonio Piras; Constanze A Jakwerth; Madlen Oelsner; Susanne Thieme; Alexander Graf; Stefan Krebs; Helmut Blum; Beate M Kümmerer; Alexey Stukalov; Carsten B Schmidt-Weber; Manabu Igarashi; Thomas Gramberg; Andreas Pichlmair; Hiroki Kato
  The EMBO journal, 41, 17, e111608, 2022年09月01日, ［国際誌］
  英語, 研究論文（学術雑誌）, The SARS-CoV-2 infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed antiviral drugs against both viral and host enzymes to pharmaceutically block methylation of the viral RNA 2'-O-ribose cap needed for viral immune escape. We find that the host cap 2'-O-ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS-CoV-2 replication. Using in silico target-based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti-SARS-CoV-2 activity in vitro and in vivo but with unfavorable side effects. We further show antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co-substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is antiviral in in vitro, in ex vivo, and in a mouse infection model and synergizes with existing COVID-19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection-induced hyperinflammation and reduces lung fibrosis markers ex vivo. Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID-19.
• Influenza A Virus Agnostic Receptor Tropism Revealed Using a Novel Biological System with Terminal Sialic Acid Knockout Cells.
  Haruhiko Kamiki; Shin Murakami; Takashi Nishikaze; Takahiro Hiono; Manabu Igarashi; Yuki Furuse; Hiromichi Matsugo; Hiroho Ishida; Misa Katayama; Wataru Sekine; Yasushi Muraki; Masateru Takahashi; Akiko Takenaka-Uema; Taisuke Horimoto
  Journal of virology, e0041622, 2022年07月18日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Avian or human influenza A viruses bind preferentially to avian- or human-type sialic acid receptors, respectively, indicating that receptor tropism is an important factor for determining the viral host range. However, there are currently no reliable methods for analyzing receptor tropism biologically under physiological conditions. In this study, we established a novel system using MDCK cells with avian- or human-type sialic acid receptors and with both sialic acid receptors knocked out (KO). When we examined the replication of human and avian influenza viruses in these KO cells, we observed unique viral receptor tropism that could not be detected using a conventional solid-phase sialylglycan binding assay, which directly assesses physical binding between the virus and sialic acids. Furthermore, we serially passaged an engineered avian-derived H4N5 influenza virus, whose PB2 gene was deleted, in avian-type receptor KO cells stably expressing PB2 to select a mutant with enhanced replication in KO cells; however, its binding to human-type sialylglycan was undetectable using the solid-phase binding assay. These data indicate that a panel of sialic acid receptor KO cells could be a useful tool for determining the biological receptor tropism of influenza A viruses. Moreover, the PB2KO virus experimental system could help to safely and efficiently identify the mutations required for avian influenza viruses to adapt to human cells that could trigger a new influenza pandemic. IMPORTANCE The acquisition of mutations that allow avian influenza A virus hemagglutinins to recognize human-type receptors is mandatory for the transmission of avian viruses to humans, which could lead to a pandemic. In this study, we established a novel system using a set of genetically engineered MDCK cells with knocked out sialic acid receptors to biologically evaluate the receptor tropism for influenza A viruses. Using this system, we observed unique receptor tropism in several virus strains that was undetectable using conventional solid-phase binding assays that measure physical binding between the virus and artificially synthesized sialylglycans. This study contributes to elucidation of the relationship between the physical binding of virus and receptor and viral infectivity. Furthermore, the system using sialic acid knockout cells could provide a useful tool to explore the sialic acid-independent entry mechanism. In addition, our system could be safely used to identify mutations that could acquire human-type receptor tropism.
• Human ACE2 Genetic Polymorphism Affecting SARS-CoV and SARS-CoV-2 Entry into Cells
  Takanari Hattori; Takeshi Saito; Kosuke Okuya; Yuji Takahashi; Hiroko Miyamoto; Masahiro Kajihara; Manabu Igarashi; Ayato Takada
  Microbiology Spectrum, American Society for Microbiology, 2022年07月11日
  研究論文（学術雑誌）, SARS-CoV and SARS-CoV-2 are known to cause severe pneumonia in humans. The S protein of these CoVs binds to the ACE2 molecule on the plasma membrane and mediates virus entry into cells.
• Mapping of Antibody Epitopes on the Crimean-Congo Hemorrhagic Fever Virus Nucleoprotein.
  Boniface Pongombo Lombe; Takeshi Saito; Hiroko Miyamoto; Akina Mori-Kajihara; Masahiro Kajihara; Masayuki Saijo; Justin Masumu; Takanari Hattori; Manabu Igarashi; Ayato Takada
  Viruses, 14, 3, 2022年03月06日, ［国際誌］
  英語, 研究論文（学術雑誌）, Crimean-Congo hemorrhagic fever virus (CCHFV), a nairovirus, is a tick-borne zoonotic virus that causes hemorrhagic fever in humans. The CCHFV nucleoprotein (NP) is the antigen most used for serological screening of CCHFV infection in animals and humans. To gain insights into antibody epitopes on the NP molecule, we produced recombinant chimeric NPs between CCHFV and Nairobi sheep disease virus (NSDV), which is another nairovirus, and tested rabbit and mouse antisera/immune ascites, anti-NP monoclonal antibodies, and CCHFV-infected animal/human sera for their reactivities to the NP antigens. We found that the amino acids at positions 161-320 might include dominant epitopes recognized by anti-CCHFV IgG antibodies, whereas cross-reactivity between anti-CCHFV and anti-NSDV antibodies was limited. Their binding capacities were further tested using a series of synthetic peptides whose sequences were derived from CCHFV NP. IgG antibodies in CCHFV-infected monkeys and patients were reactive to some of the synthetic peptide antigens (e.g., amino acid residues at positions 131-150 and 211-230). Only a few peptides were recognized by IgG antibodies in the anti-NSDV serum. These results provide useful information to improve NP-based antibody detection assays as well as antigen detection tests relying on anti-NP monoclonal antibodies.
• Structural insight into Marburg virus nucleoprotein-RNA complex formation.
  Yoko Fujita-Fujiharu; Yukihiko Sugita; Yuki Takamatsu; Kazuya Houri; Manabu Igarashi; Yukiko Muramoto; Masahiro Nakano; Yugo Tsunoda; Ichiro Taniguchi; Stephan Becker; Takeshi Noda
  Nature communications, 13, 1, 1191, 1191, 2022年03月04日, ［国際誌］
  英語, 研究論文（学術雑誌）, The nucleoprotein (NP) of Marburg virus (MARV), a close relative of Ebola virus (EBOV), encapsidates the single-stranded, negative-sense viral genomic RNA (vRNA) to form the helical NP-RNA complex. The NP-RNA complex constitutes the core structure for the assembly of the nucleocapsid that is responsible for viral RNA synthesis. Although appropriate interactions among NPs and RNA are required for the formation of nucleocapsid, the structural basis of the helical assembly remains largely elusive. Here, we show the structure of the MARV NP-RNA complex determined using cryo-electron microscopy at a resolution of 3.1 Å. The structures of the asymmetric unit, a complex of an NP and six RNA nucleotides, was very similar to that of EBOV, suggesting that both viruses share common mechanisms for the nucleocapsid formation. Structure-based mutational analysis of both MARV and EBOV NPs identified key residues for helical assembly and subsequent viral RNA synthesis. Importantly, most of the residues identified were conserved in both viruses. These findings provide a structural basis for understanding the nucleocapsid formation and contribute to the development of novel antivirals against MARV and EBOV.
• Theoretical insights into the molecular mechanism of I117V mutation in neuraminidase mediated reduction of oseltamivir drug susceptibility in A/H5N1 influenza virus
  Mohini Yadav; Manabu Igarashi; Norifumi Yamamoto
  PeerJ Physical Chemistry, 3, e19, e19, PeerJ, 2021年11月22日
  研究論文（学術雑誌）, The substitution of Ile to Val at residue 117 (I117V) of neuraminidase (NA) reduces the susceptibility of the A/H5N1 influenza virus to oseltamivir (OTV). However, the molecular mechanism by which the I117V mutation affects the intermolecular interactions between NA and OTV has not been fully elucidated. In this study, we performed molecular dynamics (MD) simulations to analyze the characteristic conformational changes that contribute to the reduced binding affinity of NA to OTV after the I117V mutation. The results of MD simulations revealed that after the I117V mutation in NA, the changes in the secondary structure around the mutation site had a noticeable effect on the residue interactions in the OTV-binding site. In the case of the WT NA-OTV complex, the positively charged side chain of R118, located in the β-sheet region, frequently interacted with the negatively charged side chain of E119, which is an amino acid residue in the OTV-binding site. This can reduce the electrostatic repulsion of E119 toward D151, which is also a negatively charged residue in the OTV-binding site, so that both E119 and D151 simultaneously form hydrogen bonds with OTV more frequently, which greatly contributes to the binding affinity of NA to OTV. After the I117V mutation in NA, the side chain of R118 interacted with the side chain of E119 less frequently, likely because of the decreased tendency of R118 to form a β-sheet structure. As a result, the electrostatic repulsion of E119 toward D151 is greater than that of the WT case, making it difficult for both E119 and D151 to simultaneously form hydrogen bonds with OTV, which in turn reduces the binding affinity of NA to OTV. Hence, after the I117V mutation in NA, influenza viruses are less susceptible to OTV because of conformational changes in residues of R118, E119, and D151 around the mutation site and in the binding site.
• Functional Importance of Hydrophobic Patches on the Ebola Virus VP35 IFN-Inhibitory Domain.
  Nodoka Kasajima; Keita Matsuno; Hiroko Miyamoto; Masahiro Kajihara; Manabu Igarashi; Ayato Takada
  Viruses, 13, 11, 2021年11月20日, ［国際誌］
  英語, 研究論文（学術雑誌）, Viral protein 35 (VP35) of Ebola virus (EBOV) is a multifunctional protein that mainly acts as a viral polymerase cofactor and an interferon antagonist. VP35 interacts with the viral nucleoprotein (NP) and double-stranded RNA for viral RNA transcription/replication and inhibition of type I interferon (IFN) production, respectively. The C-terminal portion of VP35, which is termed the IFN-inhibitory domain (IID), is important for both functions. To further identify critical regions in this domain, we analyzed the physical properties of the surface of VP35 IID, focusing on hydrophobic patches, which are expected to be functional sites that are involved in interactions with other molecules. Based on the known structural information of VP35 IID, three hydrophobic patches were identified on its surface and their biological importance was investigated using minigenome and IFN-β promoter-reporter assays. Site-directed mutagenesis revealed that some of the amino acid substitutions that were predicted to disrupt the hydrophobicity of the patches significantly decreased the efficiency of viral genome replication/transcription due to reduced interaction with NP, suggesting that the hydrophobic patches might be critical for the formation of a replication complex through the interaction with NP. It was also found that the hydrophobic patches were involved in the IFN-inhibitory function of VP35. These results highlight the importance of hydrophobic patches on the surface of EBOV VP35 IID and also indicate that patch analysis is useful for the identification of amino acid residues that directly contribute to protein functions.
• Characteristics of Classical Swine Fever Virus Variants Derived from Live Attenuated GPE- Vaccine Seed.
  Taksoo Kim; Loc Tan Huynh; Shizuka Hirose; Manabu Igarashi; Takahiro Hiono; Norikazu Isoda; Yoshihiro Sakoda
  Viruses, 13, 8, 2021年08月23日, ［国際誌］
  英語, 研究論文（学術雑誌）, The GPE- strain is a live attenuated vaccine for classical swine fever (CSF) developed in Japan. In the context of increasing attention for the differentiating infected from vaccinated animals (DIVA) concept, the achievement of CSF eradication with the GPE- proposes it as a preferable backbone for a recombinant CSF marker vaccine. While its infectious cDNA clone, vGPE-, is well characterized, 10 amino acid substitutions were recognized in the genome, compared to the original GPE- vaccine seed. To clarify the GPE- seed availability, this study aimed to generate and characterize a clone possessing the identical amino acid sequence to the GPE- seed. The attempt resulted in the loss of the infectious GPE- seed clone production due to the impaired replication by an amino acid substitution in the viral polymerase NS5B. Accordingly, replication-competent GPE- seed variant clones were produced. Although they were mostly restricted to propagate in the tonsils of pigs, similarly to vGPE-, their type I interferon-inducing capacity was significantly lower than that of vGPE-. Taken together, vGPE- mainly retains ideal properties for the CSF vaccine, compared with the seed variants, and is probably useful in the development of a CSF marker vaccine.
• Structural Insights into the Interaction of Filovirus Glycoproteins with the Endosomal Receptor Niemann-Pick C1: A Computational Study
  Manabu Igarashi; Takatsugu Hirokawa; Yoshihiro Takadate; Ayato Takada
  Viruses, 13, 5, 913, 913, 2021年05月14日
  研究論文（学術雑誌）
• The VKORC1 ER-luminal loop mutation (Leu76Pro) leads to a significant resistance to warfarin in black rats (Rattus rattus).
  Kazuki Takeda; Yoshinori Ikenaka; Denis Fourches; Kazuyuki D Tanaka; Shouta M M Nakayama; Dhoha Triki; Xinhao Li; Manabu Igarashi; Tsutomu Tanikawa; Mayumi Ishizuka
  Pesticide biochemistry and physiology, 173, 104774, 104774, 2021年03月, ［国際誌］
  英語, 研究論文（学術雑誌）, Well-known 4-hydroxycoumarin derivatives, such as warfarin, act as inhibitors of the vitamin K epoxide reductase (VKOR) and are used as anticoagulants. Mutations of the VKOR enzyme can lead to resistance to those compounds. This has been a problem in using them as medicine or rodenticide. Most of these mutations lie in the vicinity of potential warfarin-binding sites within the ER-luminal loop structure (Lys30, Phe55) and the transmembrane helix (Tyr138). However, a VKOR mutation found in Tokyo in warfarin-resistant rats does not follow that pattern (Leu76Pro), and its effect on VKOR function and structure remains unclear. We conducted both in vitro kinetic analyses and in silico docking studies to characterize the VKOR mutant. On the one hand, resistant rats (R-rats) showed a 37.5-fold increased IC50 value to warfarin when compared to susceptible rats (S-rats); on the other hand, R-rats showed a 16.5-fold lower basal VKOR activity (Vmax/Km). Docking calculations exhibited that the mutated VKOR of R-rats has a decreased affinity for warfarin. Molecular dynamics simulations further revealed that VKOR-associated warfarin was more exposed to solvents in R-rats and key interactions between Lys30, Phe55, and warfarin were less favored. This study concludes that a single mutation of VKOR at position 76 leads to a significant resistance to warfarin by modifying the types and numbers of intermolecular interactions between the two.
• Dynamic residue interaction network analysis of the oseltamivir binding site of N1 neuraminidase and its H274Y mutation site conferring drug resistance in influenza A virus.
  Mohini Yadav; Manabu Igarashi; Norifumi Yamamoto
  PeerJ, 9, e11552, 2021年, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Oseltamivir (OTV)-resistant influenza virus exhibits His-to-Tyr mutation at residue 274 (H274Y) in N1 neuraminidase (NA). However, the molecular mechanisms by which the H274Y mutation in NA reduces its binding affinity to OTV have not been fully elucidated. METHODS: In this study, we used dynamic residue interaction network (dRIN) analysis based on molecular dynamics simulation to investigate the correlation between the OTV binding site of NA and its H274Y mutation site. RESULTS: dRIN analysis revealed that the OTV binding site and H274Y mutation site of NA interact via the three interface residues connecting them. H274Y mutation significantly enhanced the interaction between residue 274 and the three interface residues in NA, thereby significantly decreasing the interaction between OTV and its surrounding loop 150 residues. Thus, we concluded that such changes in residue interactions could reduce the binding affinity of OTV to NA, resulting in drug resistant influenza viruses. Using dRIN analysis, we succeeded in understanding the characteristic changes in residue interactions due to H274Y mutation, which can elucidate the molecular mechanism of reduction in OTV binding affinity to influenza NA. Finally, the dRIN analysis used in this study can be widely applied to various systems such as individual proteins, protein-ligand complexes, and protein-protein complexes, to characterize the dynamic aspects of the interactions.
• The Polarity of an Amino Acid at Position 1891 of Severe Fever with Thrombocytopenia Syndrome Virus L Protein Is Critical for the Polymerase Activity.
  Kisho Noda; Yoshimi Tsuda; Fumiya Kozawa; Manabu Igarashi; Kenta Shimizu; Jiro Arikawa; Kumiko Yoshimatsu
  Viruses, 13, 1, 2020年12月27日, ［国際誌］
  英語, 研究論文（学術雑誌）, Severe fever with thrombocytopenia syndrome virus subclone B7 shows strong plaque formation and cytopathic effect induction compared with other subclones and the parental strain YG1. Compared to YG1 and the other subclones, only B7 possesses a single substitution in the L protein at the amino acid position 1891, in which N is changed to K (N1891K). In this study, we evaluate the effects of this mutation on L protein activity via a cell-based minigenome assay. Substitutions of N with basic amino acids (K or R) enhanced polymerase activity, while substitutions with an acidic amino acid (E) decreased this activity. Mutation to other neutral amino acids showed no significant effect on activity. These results suggest that the characteristic of the amino acid at position 1891 of the L protein are critical for its function, especially with respect to the charge status. Our data indicate that this C-terminal domain of the L protein may be crucial to its functions in genome transcription and viral replication.
• Artificially Edited Alleles of the Eukaryotic Translation Initiation Factor 4E1 Gene Differentially Reduce Susceptibility to Cucumber Mosaic Virus and Potato Virus Y in Tomato
  Hiroki Atarashi; Wikum Harshana Jayasinghe; Joon Kwon; Hangil Kim; Yosuke Taninaka; Manabu Igarashi; Kotaro Ito; Tetsuya Yamada; Chikara Masuta; Kenji S. Nakahara
  Frontiers in Microbiology, 11, Frontiers Media SA, 2020年12月10日
  研究論文（学術雑誌）, Eukaryotic translation initiation factors, including eIF4E, are susceptibility factors for viral infection in host plants. Mutation and double-stranded RNA-mediated silencing of tomato eIF4E genes can confer resistance to viruses, particularly members of the Potyvirus genus. Here, we artificially mutated the eIF4E1 gene on chromosome 3 of a commercial cultivar of tomato (Solanum lycopersicum L.) by using CRISPR/Cas9. We obtained three alleles, comprising two deletions of three and nine nucleotides (3DEL and 9DEL) and a single nucleotide insertion (1INS), near regions that encode amino acid residues important for binding to the mRNA 5' cap structure and to eIF4G. Plants homozygous for these alleles were termed 3DEL, 9DEL, and 1INS plants, respectively. In accordance with previous studies, inoculation tests with potato virus Y (PVY; type member of the genus Potyvirus) yielded a significant reduction in susceptibility to the N strain (PVY^N), but not to the ordinary strain (PVY^O), in 1INS plants. 9DEL among three artificial alleles had a deleterious effect on infection by cucumber mosaic virus (CMV, type member of the genus Cucumovirus). When CMV was mechanically inoculated into tomato plants and viral coat accumulation was measured in the non-inoculated upper leaves, the level of viral coat protein was significantly lower in the 9DEL plants than in the parental cultivar. Tissue blotting of microperforated inoculated leaves of the 9DEL plants revealed significantly fewer infection foci compared with those of the parental cultivar, suggesting that 9DEL negatively affects the initial steps of infection with CMV in a mechanically inoculated leaf. In laboratory tests, viral aphid transmission from an infected susceptible plant to 9DEL plants was reduced compared with the parental control. Although many pathogen resistance genes have been discovered in tomato and its wild relatives, no CMV resistance genes have been used in practice. RNA silencing of eIF4E expression has previously been reported to not affect susceptibility to CMV in tomato. Our findings suggest that artificial gene editing can introduce additional resistance to that achieved with mutagenesis breeding, and that edited eIF4E alleles confer an alternative way to manage CMV in tomato fields.
• A biaryl sulfonamide derivative as a novel inhibitor of filovirus infection.
  Mao Isono; Wakako Furuyama; Makoto Kuroda; Tatsunari Kondoh; Manabu Igarashi; Masahiro Kajihara; Reiko Yoshida; Rashid Manzoor; Kosuke Okuya; Hiroko Miyamoto; Heinz Feldmann; Andrea Marzi; Masahiro Sakaitani; Asuka Nanbo; Ayato Takada
  Antiviral research, 183, 104932, 104932, 2020年11月, ［国際誌］
  英語, 研究論文（学術雑誌）, Ebolaviruses and marburgviruses, members of the family Filoviridae, are known to cause fatal diseases often associated with hemorrhagic fever. Recent outbreaks of Ebola virus disease in West African countries and the Democratic Republic of the Congo have made clear the urgent need for the development of therapeutics and vaccines against filoviruses. Using replication-incompetent vesicular stomatitis virus (VSV) pseudotyped with the Ebola virus (EBOV) envelope glycoprotein (GP), we screened a chemical compound library to obtain new drug candidates that inhibit filoviral entry into target cells. We discovered a biaryl sulfonamide derivative that suppressed in vitro infection mediated by GPs derived from all known human-pathogenic filoviruses. To determine the inhibitory mechanism of the compound, we monitored each entry step (attachment, internalization, and membrane fusion) using lipophilic tracer-labeled ebolavirus-like particles and found that the compound efficiently blocked fusion between the viral envelope and the endosomal membrane during cellular entry. However, the compound did not block the interaction of GP with the Niemann-Pick C1 protein, which is believed to be the receptor of filoviruses. Using replication-competent VSVs pseudotyped with EBOV GP, we selected escape mutants and identified two EBOV GP amino acid residues (positions 47 and 66) important for the interaction with this compound. Interestingly, these amino acid residues were located at the base region of the GP trimer, suggesting that the compound might interfere with the GP conformational change required for membrane fusion. These results suggest that this biaryl sulfonamide derivative is a novel fusion inhibitor and a possible drug candidate for the development of a pan-filovirus therapeutic.
• Receptor-Mediated Host Cell Preference of a Bat-Derived Filovirus, Lloviu Virus.
  Yoshihiro Takadate; Rashid Manzoor; Takeshi Saito; Yurie Kida; Junki Maruyama; Tatsunari Kondoh; Hiroko Miyamoto; Hirohito Ogawa; Masahiro Kajihara; Manabu Igarashi; Ayato Takada
  Microorganisms, 8, 10, 2020年10月05日, ［国際誌］
  英語, 研究論文（学術雑誌）, Lloviu virus (LLOV), a bat-derived filovirus that is phylogenetically distinct from human pathogenic filoviruses such as Ebola virus (EBOV) and Marburg virus (MARV), was discovered in Europe. However, since infectious LLOV has never been isolated, the biological properties of this virus remain poorly understood. We found that vesicular stomatitis virus (VSV) pseudotyped with the glycoprotein (GP) of LLOV (VSV-LLOV) showed higher infectivity in one bat (Miniopterus sp.)-derived cell line than in the other bat-derived cell lines tested, which was distinct from the tropism of VSV pseudotyped with EBOV (VSV-EBOV) and MARV GPs. We then focused on the interaction between GP and Niemann-Pick C1 (NPC1) protein, one of the cellular receptors of filoviruses. We introduced the Miniopterus bat and human NPC1 genes into NPC1-knockout Vero E6 cells and their susceptibilities to the viruses were compared. The cell line expressing the bat NPC1 showed higher susceptibility to VSV-LLOV than that expressing human NPC1, whereas the opposite preference was seen for VSV-EBOV. Using a site-directed mutagenesis approach, amino acid residues involved in the differential tropism were identified in the NPC1 and GP molecules. Our results suggest that the interaction between GP and NPC1 is an important factor in the tropism of LLOV to a particular bat species.
• Genetic and antigenic characterization of H5 and H7 avian influenza viruses isolated from migratory waterfowl in Mongolia from 2017 to 2019.
  Ankhanbaatar Ulaankhuu; Enkhbold Bazarragchaa; Masatoshi Okamatsu; Takahiro Hiono; Khishgee Bodisaikhan; Tsolmon Amartuvshin; Jargalsaikhan Tserenjav; Tsogtbaatar Urangoo; Khanui Buyantogtokh; Keita Matsuno; Takanari Hattori; Tatsunari Kondoh; Masahiro Sato; Yoshihiro Takadate; Shiho Torii; Mao Isono; Kosuke Okuya; Takeshi Saito; Nodoka Kasajima; Yurie Kida; Junki Maruyama; Manabu Igarashi; Ayato Takada; Hiroshi Kida; Damdinjav Batchuluun; Yoshihiro Sakoda
  Virus genes, 56, 4, 472, 479, 2020年08月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, The circulation of highly pathogenic avian influenza viruses (HPAIVs) of various subtypes (e.g., H5N1, H5N6, H5N8, and H7N9) in poultry remains a global concern for animal and public health. Migratory waterfowls play important roles in the transmission of these viruses across countries. To monitor virus spread by wild birds, active surveillance for avian influenza in migratory waterfowl was conducted in Mongolia from 2015 to 2019. In total, 5000 fecal samples were collected from lakesides in central Mongolia, and 167 influenza A viruses were isolated. Two H5N3, four H7N3, and two H7N7 viruses were characterized in this study. The amino acid sequence at hemagglutinin (HA) cleavage site of those isolates suggested low pathogenicity in chickens. Phylogenetic analysis revealed that all H5 and H7 viruses were closely related to recent H5 and H7 low pathogenic avian influenza viruses (LPAIVs) isolated from wild birds in Asia and Europe. Antigenicity of H7Nx was similar to those of typical non-pathogenic avian influenza viruses (AIVs). While HPAIVs or A/Anhui/1/2013 (H7N9)-related LPAIVs were not detected in migratory waterfowl in Mongolia, sporadic introductions of AIVs including H5 and H7 viruses into Mongolia through the wild bird migration were identified. Thus, continued monitoring of H5 and H7 AIVs in both domestic and wild birds is needed for the early detection of HPAIVs spread into the country.
• Niemann-Pick C1 Heterogeneity of Bat Cells Controls Filovirus Tropism.
  Yoshihiro Takadate; Tatsunari Kondoh; Manabu Igarashi; Junki Maruyama; Rashid Manzoor; Hirohito Ogawa; Masahiro Kajihara; Wakako Furuyama; Masahiro Sato; Hiroko Miyamoto; Reiko Yoshida; Terence E Hill; Alexander N Freiberg; Heinz Feldmann; Andrea Marzi; Ayato Takada
  Cell reports, 30, 2, 308, 319, 2020年01月14日, ［査読有り］, ［国際誌］
  英語, Fruit bats are suspected to be natural hosts of filoviruses, including Ebola virus (EBOV) and Marburg virus (MARV). Interestingly, however, previous studies suggest that these viruses have different tropisms depending on the bat species. Here, we show a molecular basis underlying the host-range restriction of filoviruses. We find that bat-derived cell lines FBKT1 and ZFBK13-76E show preferential susceptibility to EBOV and MARV, respectively, whereas the other bat cell lines tested are similarly infected with both viruses. In FBKT1 and ZFBK13-76E, unique amino acid (aa) sequences are found in the Niemann-Pick C1 (NPC1) protein, one of the cellular receptors interacting with the filovirus glycoprotein (GP). These aa residues, as well as a few aa differences between EBOV and MARV GPs, are crucial for the differential susceptibility to filoviruses. Taken together, our findings indicate that the heterogeneity of bat NPC1 orthologs is an important factor controlling filovirus species-specific host tropism.
• In vivo dynamics of reporter Flaviviridae viruses.
  Tamura T; Igarashi M; Enkhbold B; Suzuki T; Okamatsu M; Ono C; Mori H; Izumi T; Sato A; Fauzyah Y; Okamoto T; Sakoda Y; Fukuhara T; Matsuura Y
  Journal of virology, 93, 22, 2019年11月15日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Recombinant viruses possessing reporter proteins have been generated for virus research. In the case of the family Flaviviridae, we recently generated recombinant viruses, including the hepatitis C virus of the genus Hepacivirus, Japanese encephalitis virus (JEV) of the genus Flavivirus, and bovine viral diarrhea virus of the genus Pestivirus; all three viruses possess an 11-amino-acid subunit derived from NanoLuc luciferase (HiBiT). Here, we further developed the recombinant viruses and investigated their utility in vivo Recombinant viruses harboring HiBiT in the E, NS1, or NS3 protein constructed based on the predicted secondary structure, solvent-accessible surface area, and root mean square fluctuation of the proteins exhibited comparable replication to that of the wild-type virus in vitro The recombinant JEV carrying HiBiT in the NS1 protein exhibited propagation in mice comparable to that of the parental virus, and propagation of the recombinant was monitored by the luciferase activity. In addition, the recombinants of classical swine fever virus (CSFV) possessing HiBiT in the Erns or E2 protein also showed propagation comparable to that of the wild-type virus. The recombinant CSFV carrying HiBiT in Erns exhibited similar replication to the parental CSFV in pigs, and detection of viral propagation of this recombinant by luciferase activity was higher than that by quantitative PCR (qPCR). Taken together, these results demonstrated that the reporter Flaviviridae viruses generated herein are powerful tools for elucidating the viral life cycle and pathogeneses and provide a robust platform for the development of novel antivirals.IMPORTANCEIn vivo applications of reporter viruses are necessary to understand viral pathogenesis and provide a robust platform for antiviral development. In developing such applications, determination of an ideal locus to accommodate foreign genes is important, because insertion of foreign genes into irrelevant loci can disrupt the protein functions required for viral replication. Here, we investigated the criteria to determine ideal insertion sites of foreign genes from the protein structure of viral proteins. The recombinant viruses generated by our criteria exhibited propagation comparable to that of parental viruses in vivo Our proteomic approach based on the flexibility profile of viral proteins may provide a useful tool for constructing reporter viruses, including Flaviviridae viruses.
• Identification of the amino acid residue important for fusion of severe fever with thrombocytopenia syndrome virus glycoprotein.
  Hideki Tani; Kengo Kawachi; Miyuki Kimura; Satoshi Taniguchi; Masayuki Shimojima; Shuetsu Fukushi; Manabu Igarashi; Shigeru Morikawa; Masayuki Saijo
  Virology, 535, 102, 110, 2019年09月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Severe fever with thrombocytopenia syndrome (SFTS) is an infectious disease with a high fatality rate, caused by SFTS virus (SFTSV). Because little is known about the nature of SFTSV, basic studies are required for the developments of vaccines and effective therapies. In the present study, we identified the amino acid residue important for membrane fusion induced by the SFTSV glycoprotein (GP). Syncytium formations were observed in cells expressing the GPs of SFTSV Japanese strain (YG-1 and SPL030). In contrast, no or only weak syncytium formations were induced in cells expressing GP of SFTSV Chinese strain (HB29). The replacement of arginine at amino acid residue 962 with serine in HB29 GP (R962S) induced membrane fusion, while the replacement of serine at residue 962 with arginine in YG1 GP (S962R) did not. These data indicate that serine at residue 962 in the SFTSV-GP is critical for inducing membrane fusion and viral infection.
• Splicing-Dependent Subcellular Targeting of Borna Disease Virus Nucleoprotein Isoforms.
  Kojima S; Sato R; Yanai M; Komatsu Y; Horie M; Igarashi M; Tomonaga K
  Journal of virology, 93, 5, 2019年03月, ［査読有り］
• Generation of bat-derived influenza viruses and their reassortants.
  Masahiro Sato; Junki Maruyama; Tatsunari Kondoh; Naganori Nao; Hiroko Miyamoto; Yoshihiro Takadate; Wakako Furuyama; Masahiro Kajihara; Hirohito Ogawa; Rashid Manzoor; Reiko Yoshida; Manabu Igarashi; Ayato Takada
  Scientific reports, 9, 1, 1158, 1158, 2019年02月04日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Two novel influenza A virus-like genomes were detected in fruit bats in Central and South America. However, the biological properties of these bat-derived influenza viruses (BatIVs) are still largely unknown since infectious viral particles have never been isolated from the infected host species. In this study, a reverse genetics approach was used to generate infectious BatIV particles entirely from plasmids encoding full-length sequences in eight gene segments. We inoculated BatIV particles into various cell cultures including bat-derived cell lines and found that BatIVs infected particular bat-derived cells efficiently but not the other cell lines tested. Reassortant viruses between the two BatIVs were also successfully generated and their replication in the susceptible bat cell lines was confirmed. These findings suggest a limited host range and reassortment potential of BatIVs in nature, providing fundamental information for understanding of the ecology of BatIVs.
• Recombination and purifying and balancing selection determine the evolution of major antigenic protein 1 (map 1) family genes in Ehrlichia ruminantium.
  Salim B; Amin M; Igarashi M; Ito K; Jongejan F; Katakura K; Sugimoto C; Nakao R
  Gene, 683, 216, 224, Elsevier BV, 2019年01月, ［査読有り］
  研究論文（学術雑誌）
• Single-Nucleotide Polymorphisms in Human NPC1 Influence Filovirus Entry Into Cells.
  Tatsunari Kondoh; Michael Letko; Vincent J Munster; Rashid Manzoor; Junki Maruyama; Wakako Furuyama; Hiroko Miyamoto; Asako Shigeno; Daisuke Fujikura; Yoshihiro Takadate; Reiko Yoshida; Manabu Igarashi; Heinz Feldmann; Andrea Marzi; Ayato Takada
  The Journal of infectious diseases, 218, suppl_5, S397-S402, 2018年11月22日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Niemann-Pick C1 (NPC1), a host receptor involved in the envelope glycoprotein (GP)-mediated entry of filoviruses into cells, is believed to be a major determinant of cell susceptibility to filovirus infection. It is known that proteolytically digested Ebola virus (EBOV) GP interacts with 2 protruding loops in domain C of NPC1. Using previously published structural data and the National Center for Biotechnology Information Single-Nucleotide Polymorphism (SNP) database, we identified 10 naturally occurring missense SNPs in human NPC1. To investigate whether these SNPs affect cell susceptibility to filovirus infection, we generated Vero E6 cell lines stably expressing NPC1 with SNP substitutions and compared their susceptibility to vesicular stomatitis virus pseudotyped with filovirus GPs and infectious EBOV. We found that some of the substitutions resulted in reduced susceptibility to filoviruses, as indicated by the lower titers and smaller plaque/focus sizes of the viruses. Our data suggest that human NPC1 SNPs may likely affect host susceptibility to filoviruses.
• Two Conserved Amino Acids within the NSs of Severe Fever with Thrombocytopenia Syndrome Phlebovirus Are Essential for Anti-interferon Activity.
  Moriyama M; Igarashi M; Koshiba T; Irie T; Takada A; Ichinohe T
  Journal of virology, 92, 19, 2018年10月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, The nonstructural protein (NSs) of severe fever with thrombocytopenia syndrome phlebovirus (SFTSV) sequesters TANK-binding kinase 1 (TBK1) into NSs-induced cytoplasmic structures to inhibit the phosphorylation and nuclear translocation of interferon (IFN) regulatory factor 3 (IRF3) and subsequent interferon beta (IFN-β) production. Although the C-terminal region of SFTSV NSs (NSs66-249) has been linked to the formation of NSs-induced cytoplasmic structures and inhibition of host IFN-β responses, the role of the N-terminal region in antagonizing host antiviral responses remains to be defined. Here, we demonstrate that two conserved amino acids at positions 21 and 23 in the SFTSV and heartland virus (HRTV) NSs are essential for suppression of IRF3 phosphorylation and IFN-β mRNA expression following infection with SFTSV or recombinant influenza virus lacking the NS1 gene. Surprisingly, formation of SFTSV/HRTV NSs-induced cytoplasmic structures is not essential for inhibition of host antiviral responses. Rather, an association between SFTSV/HRTV NSs and TBK1 is required for suppression of mitochondrial antiviral signaling protein (MAVS)-mediated activation of IFN-β promoter activity. Although SFTSV NSs did not prevent the ubiquitination of TBK1, it associates with TBK1 through its N-terminal kinase domain (residues 1 to 307) to block the autophosphorylation of TBK1. Furthermore, we found that both wild-type NSs and the 21/23A mutant (NSs in which residues at positions 21 and 23 were replaced with alanine) of SFTSV suppressed NLRP3 inflammasome-dependent interleukin-1β (IL-1β) secretion, suggesting that the importance of these residues is restricted to TBK1-dependent IFN signaling. Together, our findings strongly implicate the two conserved amino acids at positions 21 and 23 of SFTSV/HRTV NSs in the inhibition of host interferon responses.IMPORTANCE Recognition of viruses by host innate immune systems plays a critical role not only in providing resistance to viral infection but also in the initiation of antigen-specific adaptive immune responses against viruses. Severe fever with thrombocytopenia syndrome (SFTS) is a newly emerging infectious disease caused by the SFTS phlebovirus (SFTSV), a highly pathogenic tick-borne phlebovirus. The 294-amino-acid nonstructural protein (NSs) of SFTSV associates with TANK-binding kinase 1 (TBK1), a key regulator of host innate antiviral immunity, to inhibit interferon beta (IFN-β) production and enhance viral replication. Here, we demonstrate that two conserved amino acids at positions 21 and 23 in the NSs of SFTSV and heartland virus, another tick-borne phlebovirus, are essential for association with TBK1 and suppression of IFN-β production. Our results provide important insight into the molecular mechanisms by which SFTSV NSs helps to counteract host antiviral strategies.
• Structural Characterization of Pan-ebolavirus Antibody 6D6 Targeting the Fusion Peptide of the Surface Glycoprotein.
  Milligan JC; Parekh DV; Fuller KM; Igarashi M; Takada A; Saphire EO
  The Journal of infectious diseases, 219, 3, 415, 419, 2018年09月, ［査読有り］
• The Unique Phylogenetic Position of a Novel Tick-Borne Phlebovirus Ensures an Ixodid Origin of the Genus Phlebovirus.
  Keita Matsuno; Masahiro Kajihara; Ryo Nakao; Naganori Nao; Akina Mori-Kajihara; Mieko Muramatsu; Yongjin Qiu; Shiho Torii; Manabu Igarashi; Nodoka Kasajima; Keita Mizuma; Kentaro Yoshii; Hirofumi Sawa; Chihiro Sugimoto; Ayato Takada; Hideki Ebihara
  mSphere, 3, 3, 2018年06月27日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, The recent emergence of novel tick-borne RNA viruses has complicated the epidemiological landscape of tick-borne infectious diseases, posing a significant challenge to public health systems that seek to counteract tick-borne diseases. The identification of two novel tick-borne phleboviruses (TBPVs), severe fever with thrombocytopenia syndrome virus (SFTSV) and Heartland virus (HRTV), as causative agents of severe illness in humans has accelerated the investigation and discoveries of novel TBPVs. In the present study, we isolated a novel TBPV designated Mukawa virus (MKWV) from host-questing Ixodes persulcatus females captured in Japan. Genetic characterization revealed that MKWV is a member of the genus Phlebovirus in the family Phenuiviridae Interestingly, MKWV is genetically distinct from other known TBPVs and shares a most recent common ancestor with mosquito/sandfly-borne (insect-borne) phleboviruses. Despite its genetic similarity to insect-borne phleboviruses, the molecular footprints of its viral proteins and its biological characteristics define MKWV as a tick-borne virus that can be transmitted to mammals. A phylogenetic ancestral-state reconstruction for arthropod vectors of phleboviruses including MKWV based on viral L segment sequences indicated that ticks likely harbored ancestral phleboviruses that evolved into both the tick-borne and MKWV/insect-borne phlebovirus lineages. Overall, our findings suggest that most of the phlebovirus evolution has occurred in hard ticks to generate divergent viruses, which may provide a seminal foundation for understanding the mechanisms underlying the evolution and emergence of pathogenic phleboviruses, such as Rift Valley fever virus and SFTSV/HRTV.IMPORTANCE The emergence of novel tick-borne RNA viruses causing severe illness in humans has complicated the epidemiological landscape of tick-borne diseases, requiring further investigation to safeguard public health. In the present study, we discovered a novel tick-borne phlebovirus from Ixodes persulcatus ticks in Japan. While its viral RNA genome sequences were similar to those of mosquito/sandfly-borne viruses, molecular and biological footprints confirmed that this is a tick-borne virus. The unique evolutionary position of the virus allowed us to estimate the ancestral phlebovirus vector, which was likely a hard tick. Our findings may provide a better understanding of the evolution and emergence of phleboviruses associated with emerging infectious diseases, such as severe fever with thrombocytopenia syndrome (SFTS) and Heartland virus disease.
• Influenza A virus M2 protein: Roles from ingress to egress
  Rashid Manzoor; Manabu Igarashi; Ayato Takada
  International Journal of Molecular Sciences, 18, 12, MDPI AG, 2017年12月07日, ［査読有り］
  英語, 研究論文（学術雑誌）
• Escape of Tick-Borne Flavivirus from 2'-C-Methylated Nucleoside Antivirals Is Mediated by a Single Conservative Mutation in NS5 That Has a Dramatic Effect on Viral Fitness
  Ludek Eyer; Hirofumi Kondo; Darina Zouharova; Minato Hirano; James J. Valdes; Memi Muto; Tomas Kastl; Shintaro Kobayashi; Jan Haviernik; Manabu Igarashi; Hiroaki Kariwa; Marketa Vaculovicova; Jiri Cerny; Rene Kizek; Andrea Kroeger; Stefan Lienenklaus; Milan Dejmek; Radim Nencka; Martin Palus; Jiri Salat; Erik De Clercq; Kentaro Yoshii; Daniel Ruzek
  JOURNAL OF VIROLOGY, 91, 21, 2017年11月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Putative endogenous filovirus VP35-like protein potentially functions as an IFN antagonist but not a polymerase cofactor
  Tatsunari Kondoh; Rashid Manzoor; Naganori Nao; Junki Maruyama; Wakako Furuyama; Hiroko Miyamoto; Asako Shigeno; Makoto Kuroda; Keita Matsuno; Daisuke Fujikura; Masahiro Kajihara; Reiko Yoshida; Manabu Igarashi; Ayato Takada
  PLOS ONE, 12, 10, e0186450, 2017年10月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Host-derived apolipoproteins play comparable roles with viral secretory proteins E-rns and NS1 in the infectious particle formation of Flaviviridae
  Takasuke Fukuhara; Tomokazu Tamura; Chikako Ono; Mai Shiokawa; Hiroyuki Mori; Kentaro Uemura; Satomi Yamamoto; Takeshi Kurihara; Toru Okamoto; Ryosuke Suzuki; Kentaro Yoshii; Takeshi Kurosu; Manabu Igarashi; Hiroshi Aoki; Yoshihiro Sakoda; Yoshiharu Matsuura
  PLOS PATHOGENS, 13, 6, e1006475, 2017年06月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Genetic Predisposition To Acquire a Polybasic Cleavage Site for Highly Pathogenic Avian Influenza Virus Hemagglutinin
  Naganori Nao; Junya Yamagishi; Hiroko Miyamoto; Manabu Igarashi; Rashid Manzoor; Aiko Ohnuma; Yoshimi Tsuda; Wakako Furuyama; Asako Shigeno; Masahiro Kajihara; Noriko Kishida; Reiko Yoshida; Ayato Takada
  MBIO, 8, 1, 2017年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• The amino acid at position 624 in the glycoprotein of SFTSV (severe fever with thrombocytopenia virus) plays a critical role in low-pH-dependent cell fusion activity
  Yoshimi Tsuda; Manabu Igarashi; Ryo Ito; Sanae Nishio; Kenta Shimizu; Kumiko Yoshimatsu; Jiro Arikawa
  BIOMEDICAL RESEARCH-TOKYO, 38, 2, 89, 97, 2017年, ［査読有り］
  英語, 研究論文（学術雑誌）
• Fcγ-receptor IIa-mediated Src Signaling Pathway Is Essential for the Antibody-Dependent Enhancement of Ebola Virus Infection.
  Furuyama W; Marzi A; Carmody AB; Maruyama J; Kuroda M; Miyamoto H; Nanbo A; Manzoor R; Yoshida R; Igarashi M; Feldmann H; Takada A
  PLoS pathogens, 12, 12, e1006139, 2016年12月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Amino acid residues at positions 222 and 227 of the hemagglutinin together with the neuraminidase determine binding of H5 avian influenza viruses to sialyl Lewis X
  Takahiro Hiono; Masatoshi Okamatsu; Manabu Igarashi; Ryan McBride; Robert P. de Vries; Wenjie Peng; James C. Paulson; Yoshihiro Sakoda; Hiroshi Kida
  ARCHIVES OF VIROLOGY, 161, 2, 307, 316, 2016年02月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Discovery of an antibody for pan-ebolavirus therapy
  Wakako Furuyama; Andrea Marzi; Asuka Nanbo; Elaine Haddock; Junki Maruyama; Hiroko Miyamoto; Manabu Igarashi; Reiko Yoshida; Osamu Noyori; Heinz Feldmann; Ayato Takada
  SCIENTIFIC REPORTS, 6, 20514, 2016年02月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Characterization of the glycoproteins of bat-derived influenza viruses
  Junki Maruyama; Naganori Nao; Hiroko Miyamoto; Ken Maeda; Hirohito Ogawa; Reiko Yoshida; Manabu Igarashi; Ayato Takada
  VIROLOGY, 488, 43, 50, 2016年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Seroepidemiological Prevalence of Multiple Species of Filoviruses in Fruit Bats (Eidolon helvum) Migrating in Africa
  Hirohito Ogawa; Hiroko Miyamoto; Eri Nakayama; Reiko Yoshida; Ichiro Nakamura; Hirofumi Sawa; Akihiro Ishii; Yuka Thomas; Emiko Nakagawa; Keita Matsuno; Masahiro Kajihara; Junki Maruyama; Naganori Nao; Mieko Muramatsu; Makoto Kuroda; Edgar Simulundu; Katendi Changula; Bernard Hang'ombe; Boniface Namangala; Andrew Nambota; Jackson Katampi; Manabu Igarashi; Kimihito Ito; Heinz Feldmann; Chihiro Sugimoto; Ladslav Moonga; Aaron Mweene; Ayato Takada
  JOURNAL OF INFECTIOUS DISEASES, 212, S101, S108, 2015年10月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Intracellular membrane association of the N-terminal domain of classical swine fever virus NS4B determines viral genome replication and virulence
  Tomokazu Tamura; Nicolas Ruggli; Naofumi Nagashima; Masatoshi Okamatsu; Manabu Igarashi; Junki Mine; Martin A. Hofmann; Matthias Liniger; Artur Summerfield; Hiroshi Kida; Yoshihiro Sakoda
  JOURNAL OF GENERAL VIROLOGY, 96, 9, 2623, 2635, 2015年09月, ［査読有り］
  英語, 研究論文（学術雑誌）
• A Single Amino Acid in the M1 Protein Responsible for the Different Pathogenic Potentials of H5N1 Highly Pathogenic Avian Influenza Virus Strains
  Naganori Nao; Masahiro Kajihara; Rashid Manzoor; Junki Maruyama; Reiko Yoshida; Mieko Muramatsu; Hiroko Miyamoto; Manabu Igarashi; Nao Eguchi; Masahiro Sato; Tatsunari Kondoh; Masatoshi Okamatsu; Yoshihiro Sakoda; Hiroshi Kida; Ayato Takada
  PLOS ONE, 10, 9, e0137989, 2015年09月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Emergence of H7N9 Influenza A Virus Resistant to Neuraminidase Inhibitors in Nonhuman Primates
  Yasushi Itoh; Shintaro Shichinohe; Misako Nakayama; Manabu Igarashi; Akihiro Ishii; Hirohito Ishigaki; Hideaki Ishida; Naoko Kitagawa; Takako Sasamura; Masanori Shiohara; Michiko Doi; Hideaki Tsuchiya; Shinichiro Nakamura; Masatoshi Okamatsu; Yoshihiro Sakoda; Hiroshi Kida; Kazumasa Ogasawara
  ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 59, 8, 4962, 4973, 2015年08月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Efficient Isolation of Swine Influenza Viruses by Age-Targeted Specimen Collection
  Makoto Ozawa; Aya Matsuu; Kouki Yonezawa; Manabu Igarashi; Kosuke Okuya; Toshiko Kawabata; Kimihito Ito; Kyoko Tsukiyama-Kohara; Akira Taneno; Eisaburo Deguchi
  JOURNAL OF CLINICAL MICROBIOLOGY, 53, 4, 1331, 1338, 2015年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Protective Efficacy of Passive Immunization with Monoclonal Antibodies in Animal Models of H5N1 Highly Pathogenic Avian Influenza Virus Infection
  Yasushi Itoh; Reiko Yoshida; Shintaro Shichinohe; Megumi Higuchi; Hirohito Ishigaki; Misako Nakayama; Van Loi Pham; Hideaki Ishida; Mitsutaka Kitano; Masahiko Arikata; Naoko Kitagawa; Yachiyo Mitsuishi; Kazumasa Ogasawara; Hideaki Tsuchiya; Takahiro Hiono; Masatoshi Okamatsu; Yoshihiro Sakoda; Hiroshi Kida; Mutsumi Ito; Le Quynh Mai; Yoshihiro Kawaoka; Hiroko Miyamoto; Mari Ishijima; Manabu Igarashi; Yasuhiko Suzuki; Ayato Takada
  PLOS PATHOGENS, 10, 6, e1004192, 2014年06月, ［査読有り］
  英語, 研究論文（学術雑誌）
• A Critical Determinant of Neurological Disease Associated with Highly Pathogenic Tick-Borne Flavivirus in Mice
  Kentaro Yoshii; Yuji Sunden; Kana Yokozawa; Manabu Igarashi; Hiroaki Kariwa; Michael R. Holbrook; Ikuo Takashima
  JOURNAL OF VIROLOGY, 88, 10, 5406, 5420, 2014年05月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Closest-Neighbor Resampling for Huge Biological Sequence Datasets
  Yonezawa Kouki; Igarashi Manabu; Ohara Yasuo; Ito Kimihito
  Genes & Genetic Systems, 89, 6, 313, 2014年, ［査読有り］
• High prevalence of spotted fever group rickettsiae in Amblyomma variegatum from Uganda and their identification using sizes of intergenic spacers.
  Ryo Nakao; Yongjin Qiu; Manabu Igarashi; Joseph W Magona; Lijia Zhou; Kimihito Ito; Chihiro Sugimoto
  Ticks and tick-borne diseases, 4, 6, 506, 12, 6, 2013年12月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, The spotted fever group (SFG) rickettsiae are obligate intracellular bacteria transmitted by ticks that cause several tick-borne rickettsioses in humans worldwide. This study was intended to determine the prevalence of SFG rickettsiae in Amblyomma variegatum from 7 districts across Uganda. In addition to sequencing of gltA and ompA genes, identification of Rickettsia species based on the sizes of highly variable intergenic spacers, namely, dksA-xerC, mppA-purC, and rpmE-tRNA(fMet) was carried out. Application of multiplex PCR for simultaneous amplification of 3 spacers combined with capillary electrophoresis separation allowed simple, accurate, and high-throughput fragment sizing with considerable time and cost savings. Rickettsia genus-specific real-time PCR detected 136 positives out of 140 samples, giving an overall prevalence of 97.1%. Most samples (n=113) had a size combination of 225, 195, and 341 bp for dksA-xerC, mppA-purC, and rpmE-tRNA(fMet), respectively, which was identical to that of R. africae, a causative agent of African tick bite fever. In addition, several samples had size variants in either dksA-xerC or rpmE-tRNA(fMet). Nonetheless, the partial sequences of gltA and ompA genes of samples of all size combinations showed the greatest similarity to R. africae (99.3-100% for gltA and 98.1-100% for ompA). Given these results, it is highly possible that the tested ticks were infected with R. africae or closely related species. This is a first report on molecular genetic detection of R. africae and its high endemicity in Uganda. Clinicians in this country should be aware of this pathogen as a cause of non-malarial febrile illness. This study provided a starting point for the development of Rickettsia species identification based on the sizes of intergenic spacers. The procedure is simple, rapid, and cost-effective to perform; hence it might be particularly well suited for preliminary species identification in epidemiological investigations. The results may be more detailed and reliable when simultaneous sequencing analysis is performed.
• Differential potential for envelope glycoprotein-mediated steric shielding of host cell surface proteins among filoviruses
  Osamu Noyori; Keita Matsuno; Masahiro Kajihara; Eri Nakayama; Manabu Igarashi; Makoto Kuroda; Norikazu Isoda; Reiko Yoshida; Ayato Takada
  VIROLOGY, 446, 1-2, 152, 161, 2013年11月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Cysteine Residues in the Major Capsid Protein, Vp1, of the JC Virus Are Important for Protein Stability and Oligomer Formation
  Shintaro Kobayashi; Tadaki Suzuki; Manabu Igarashi; Yasuko Orba; Noriko Ohtake; Keita Nagakawa; Kenichi Niikura; Takashi Kimura; Harumi Kasamatsu; Hirofumi Sawa
  PLoS ONE, 8, 10, e76668, 10, 2013年10月09日, ［査読有り］
  英語, 研究論文（学術雑誌）
• Antiviral activity of stachyflin on influenza A viruses of different hemagglutinin subtypes
  Yurie Motohashi; Manabu Igarashi; Masatoshi Okamatsu; Takeshi Noshi; Yoshihiro Sakoda; Naoki Yamamoto; Kimihito Ito; Ryu Yoshida; Hiroshi Kida
  VIROLOGY JOURNAL, 10, 118, 2013年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Novel mutations in Marburg virus glycoprotein associated with viral evasion from antibody mediated immune pressure
  Masahiro Kajihara; Eri Nakayama; Andrea Marzi; Manabu Igarashi; Heinz Feldmann; Ayato Takada
  JOURNAL OF GENERAL VIROLOGY, 94, 4, 876, 883, 2013年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Resampling Nucleotide Sequences with Closest-Neighbor Trimming and Its Comparison to Other Methods
  Kouki Yonezawa; Manabu Igarashi; Keisuke Ueno; Ayato Takada; Kimihito Ito
  PLoS ONE, 8, 2, e57684, 2, 2013年02月27日, ［査読有り］
  英語, 研究論文（学術雑誌）
• Molecular Mechanisms Underlying Oseltamivir Resistance Mediated by an I117V Substitution in the Neuraminidase of Subtype H5N1 Avian Influenza A Viruses
  Ryo Takano; Maki Kiso; Manabu Igarashi; Quynh Mai Le; Masakazu Sekijima; Kimihito Ito; Ayato Takada; Yoshihiro Kawaoka
  JOURNAL OF INFECTIOUS DISEASES, 207, 1, 89, 97, 2013年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Serological Evidence of Ebola Virus Infection in Indonesian Orangutans
  Chairul A. Nidom; Eri Nakayama; Reviany V. Nidom; Mohamad Y. Alamudi; Syafril Daulay; Indi N. L. P. Dharmayanti; Yoes P. Dachlan; Mohamad Amin; Manabu Igarashi; Hiroko Miyamoto; Reiko Yoshida; Ayato Takada
  PLOS ONE, 7, 7, e40740, 2012年07月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Tobacco calmodulin-like protein provides secondary defense by binding to and directing degradation of virus RNA silencing suppressors
  Kenji S. Nakahara; Chikara Masuta; Syouta Yamada; Hanako Shimura; Yukiko Kashihara; Tomoko S. Wada; Ayano Meguro; Kazunori Goto; Kazuki Tadamura; Kae Sueda; Toru Sekiguchi; Jun Shao; Noriko Itchoda; Takeshi Matsumura; Manabu Igarashi; Kimihito Ito; Richard W. Carthew; Ichiro Uyeda
  PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 109, 25, 10113, 10118, 2012年06月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Protective Efficacy of Neutralizing Monoclonal Antibodies in a Nonhuman Primate Model of Ebola Hemorrhagic Fever
  Andrea Marzi; Reiko Yoshida; Hiroko Miyamoto; Mari Ishijima; Yasuhiko Suzuki; Megumi Higuchi; Yukie Matsuyama; Manabu Igarashi; Eri Nakayama; Makoto Kuroda; Masayuki Saijo; Friederike Feldmann; Douglas Brining; Heinz Feldmann; Ayato Takada
  PLOS ONE, 7, 4, e36192, 2012年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Virus Capsid Coating of Gold Nanoparticles via Cysteine-Au Interactions and Their Effective Cellular Uptakes
  Keita Nagakawa; Kenichi Niikura; Tadaki Suzuki; Yasutaka Matsuo; Manabu Igarashi; Hirofumi Sawa; Kuniharu Ijiro
  CHEMISTRY LETTERS, 41, 1, 113, 115, 2012年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• A conserved region in the prM protein is a critical determinant in the assembly of flavivirus particles
  Kentaro Yoshii; Manabu Igarashi; Osamu Ichii; Kana Yokozawa; Kimihito Ito; Hiroaki Kariwa; Ikuo Takashima
  JOURNAL OF GENERAL VIROLOGY, 93, 1, 27, 38, 2012年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Single Amino Acid Residue in the A2 Domain of Major Histocompatibility Complex Class I Is Involved in the Efficiency of Equine Herpesvirus-1 Entry
  Michihito Sasaki; Eunmi Kim; Manabu Igarashi; Kimihito Ito; Rie Hasebe; Hideto Fukushi; Hirofumi Sawa; Takashi Kimura
  JOURNAL OF BIOLOGICAL CHEMISTRY, 286, 45, 39370, 39378, 2011年11月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Gnarled-Trunk Evolutionary Model of Influenza A Virus Hemagglutinin
  Kimihito Ito; Manabu Igarashi; Yutaka Miyazaki; Teiji Murakami; Syaka Iida; Hiroshi Kida; Ayato Takada
  PLOS ONE, 6, 10, e25953, 2011年10月, ［査読有り］
  英語, 研究論文（学術雑誌）
• An H5N1 highly pathogenic avian influenza virus that invaded Japan through waterfowl migration
  Masahiro Kajihara; Keita Matsuno; Edgar Simulundu; Mieko Muramatsu; Osamu Noyori; Rashid Manzoor; Eri Nakayama; Manabu Igarashi; Daisuke Tomabechi; Reiko Yoshida; Masatoshi Okamatsu; Yoshihiro Sakoda; Kimihito Ito; Hiroshi Kida; Ayato Takada
  JAPANESE JOURNAL OF VETERINARY RESEARCH, 59, 2-3, 89, 100, 2011年08月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Characterization of influenza A viruses isolated from wild waterfowl in Zambia
  Edgar Simulundu; Akihiro Ishii; Manabu Igarashi; Aaron S. Mweene; Yuka Suzuki; Bernard M. Hang'ombe; Boniface Namangala; Ladslav Moonga; Rashid Manzoor; Kimihito Ito; Ichiro Nakamura; Hirofumi Sawa; Chihiro Sugimoto; Hiroshi Kida; Chuma Simukonda; Wilbroad Chansa; Jack Chulu; Ayato Takada
  JOURNAL OF GENERAL VIROLOGY, 92, 6, 1416, 1427, 2011年06月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Prediction of the antigenic changes of the pandemic (H1N1) 2009 influenza virus hemagglutinin
  Manabu Igarashi; Kimihito Ito; Reiko Yoshida; Daisuke Tomabechi; Hiroshi Kida; Ayato Takada
  INFLUENZA AND OTHER RESPIRATORY VIRUSES, 5, 402, 404, 2011年05月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Involvement of viral envelope GP2 in Ebola virus entry into cells expressing the macrophage galactose-type C-type lectin
  Katsuaki Usami; Keita Matsuno; Manabu Igarashi; Kaori Denda-Nagai; Ayato Takada; Tatsuro Irimura
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 407, 1, 74, 78, 2011年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Construction of an infectious cDNA clone for Omsk hemorrhagic fever virus, and characterization of mutations in NS2A and NS5
  Kentaro Yoshii; Manabu Igarashi; Kimihito Ito; Hiroaki Kariwa; Michael R. Holbrook; Ikuo Takashima
  VIRUS RESEARCH, 155, 1, 61, 68, 2011年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Genetic characterization and susceptibility on poultry and mammal of H7N6 subtype avian influenza virus isolated in Japan in 2009
  Yuko Uchida; Katsushi Kanehira; Masaji Mase; Nobuhiro Takemae; Chiaki Watanabe; Tatsufumi Usui; Yoshikazu Fujimoto; Toshihiro Ito; Manabu Igarashi; Kimihito Ito; Ayato Takada; Yoshihiro Sakoda; Masatoshi Okamatsu; Yu Yamamoto; Kikuyasu Nakamura; Hiroshi Kida; Yasuaki Hiromoto; Tomoyuki Tsuda; Takehiko Saito
  VETERINARY MICROBIOLOGY, 147, 1-2, 1, 10, 2011年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Enzyme-Linked Immunosorbent Assay for Detection of Filovirus Species-Specific Antibodies
  Eri Nakayama; Ayaka Yokoyama; Hiroko Miyamoto; Manabu Igarashi; Noriko Kishida; Keita Matsuno; Andrea Marzi; Heinz Feldmann; Kimihito Ito; Masayuki Saijo; Ayato Takada
  CLINICAL AND VACCINE IMMUNOLOGY, 17, 11, 1723, 1728, 2010年11月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Transcellular transport of West Nile virus-like particles across human endothelial cells depends on residues 156 and 159 of envelope protein
  Rie Hasebe; Tadaki Suzuki; Yoshinori Makino; Manabu Igarashi; Satoko Yamanouchi; Akihiko Maeda; Motohiro Horiuchi; Hirofumi Sawa; Takashi Kimura
  BMC MICROBIOLOGY, 10, 165, 2010年06月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Different Potential of C-Type Lectin-Mediated Entry between Marburg Virus Strains
  Keita Matsuno; Noriko Kishida; Katsuaki Usami; Manabu Igarashi; Reiko Yoshida; Eri Nakayama; Masayuki Shimojima; Heinz Feldmann; Tatsuro Irimura; Yoshihiro Kawaoka; Ayato Takada
  JOURNAL OF VIROLOGY, 84, 10, 5140, 5147, 2010年05月, ［査読有り］
  英語, 研究論文（学術雑誌）
• A novel copper(II) coordination at His186 in full-length murine prion protein
  Yasuko Watanabe; Wakako Hiraoka; Manabu Igarashi; Kimihito Ito; Yuhei Shimoyama; Motohiro Horiuchi; Tohru Yamamoria; Hironobu Yasui; Mikinori Kuwabara; Fuyuhiko Inagaki; Osamu Inanami
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 394, 3, 522, 528, 2010年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Predicting the Antigenic Structure of the Pandemic (H1N1) 2009 Influenza Virus Hemagglutinin
  Manabu Igarashi; Kimihito Ito; Reiko Yoshida; Daisuke Tomabechi; Hiroshi Kida; Ayato Takada
  PLOS ONE, 5, 1, e8553, 2010年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Cross-Protective Potential of a Novel Monoclonal Antibody Directed against Antigenic Site B of the Hemagglutinin of Influenza A Viruses
  Reiko Yoshida; Manabu Igarashi; Hiroichi Ozaki; Noriko Kishida; Daisuke Tomabechi; Hiroshi Kida; Kimihito Ito; Ayato Takada
  PLOS PATHOGENS, 5, 3, e1000350, 2009年03月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Prediction of N-glycosylation potential of influenza virus hemagglutinin by a bioinformatic approach
  Manabu Igarashi; Kimihito Ito; Ayato Takada
  Glycoforum, 2009年
  研究論文（学術雑誌）
• Genetically destined potentials for N-linked glycosylation of influenza virus hemagglutinin
  Manabu Igarashi; Kimihito Ito; Hiroshi Kida; Ayato Takada
  VIROLOGY, 376, 2, 323, 329, 2008年07月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Data Mining in Amino Acid Sequences of H3N2 Influenza Viruses Isolated during 1968 to 2006.
  Ito K; Igarashi M; Takada A
  Knowledge Media Technologies, 21, 154, 158, TU Ilmenau, 2006年07月, ［査読有り］
  英語, The hemagglutinin (HA) of influenza viruses undergoes antigenic drift to escape from antibody-mediated immune pressure. In order to predict possible structural changes of the HA molecules in future, it is important to understand the patterns of amino acid mutations and structural changes in the past. We performed a retrospective and comprehensive analysis of structural changes in H3 hemagglutinins of human influenza viruses isolated during 1968 to 2006. Amino acid sequence data of more than 2000 strains have been collected from NCBI Influenza virus resources. Information theoretic analysis of the collected sequences revealed a number of simultaneous mutations of amino acids at two or more different positions (correlated mutations). We also calculated the net charge of the HA1 subunit, based on thenumber of charged amino acid residues, and found that the net charge increased linearly from 1968 to 1984 and, after then, has been saturated. This level of the net charge may be an upper limit for H3 HA to be functional. It is noted that "correlated mutations" with the conversion of acidic and basic amino acid residues between two different positions were frequently found after 1984, suggesting that these mutations contributed to counterbalancing effect to keep the net charge of the HA . These approaches may open the way to find the direction of future antigenic drift of influenza viruses.
• Direct ab initio molecular dynamics study on a SN2 reaction OH- + CH3Cl → CH3OH + Cl-: Effect of non-zero impact parameter on the reaction dynamics.
  Tachikawa H; Igarashi M
  Chemical Physics, 324, 2-3, 639, 646, 2006年05月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Advocacy, promotion and e-learning: Supercourse for zoonosis
  Gino C. Matibag; Manabu Igarashi; Ron E. La Porte; Hiko Tamashiro
  Environmental Health and Preventive Medicine, 10, 5, 273, 281, 5, 2005年09月, ［査読有り］
  英語
• Strategic Approach to Information Security and Assurance in Health Research
  Shunichi Akazawa; Manabu Igarashi; Hirofumi Sawa; Hiko Tamashiro
  Environmental Health and Preventive Medicine, 10, 5, 282, 285, 5, 2005年09月, ［査読有り］
  英語
• BSE safety standards: An evaluation of public health policies of Japan, Europe, and USA
  Gino C. Matibag; Manabu Igarashi; Hiko Tamashiro
  Environmental Health and Preventive Medicine, 10, 5, 303, 314, 5, 2005年09月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Ab initio model study on acetylcholinesterase catalysis: potential energy surfaces of the proton transfer reactions
  H Tachikawa; M Igarashi; J Nishihira; T Ishibashi
  JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY, 79, 1, 11, 23, 2005年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Energetics of Catalytic Reaction of Acetylcholinesterase (AChE) with Acetylcholine (ACh): Role of Oxyanion Hole
  Igarashi M; Ishibashi T; Nishihira J; Tachikawa H
  Internet Electronic Journal of Molecular Design, 2, 712, 722, 2003年11月, ［査読有り］
• Ionization dynamics of trans-formanilide-H2O complexes: A direct ab initio dynamics study
  H Tachikawa; M Igarashi; T Ishibashi
  JOURNAL OF PHYSICAL CHEMISTRY A, 107, 38, 7505, 7513, 2003年09月, ［査読有り］
  英語, 研究論文（学術雑誌）
• A direct ab-initio trajectory study on the gas phase SN2 reaction OH- + CH3Cl → CH3OH + Cl-
  Tachikawa H; Igarashi M; Ishibashi T
  J. Phys. Chem. A, 106, 46, 10977, 10984, 2002年11月, ［査読有り］
  英語, 研究論文（学術雑誌）
• A direct ab initio molecular dynamics study of the finite temperature effects on the hyperfine coupling constant of methyl radical-water complexes
  M Igarashi; T Ishibashi; H Tachikawa
  JOURNAL OF MOLECULAR STRUCTURE-THEOCHEM, 594, 61, 69, 2002年10月, ［査読有り］
  英語, 研究論文（学術雑誌）
• A direct ab initio trajectory study on a microsolvated S(N)2 reaction F-(H2O)+CH3Cl at hyperthermal collision energy
  H Tachikawa; M Igarashi; T Ishibashi
  CHEMICAL PHYSICS LETTERS, 363, 3-4, 355, 361, 2002年09月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Ab initio molecular dynamics (MD) calculations of chyperfine coupling constants of methyl radical
  H Tachikawa; M Igarashi; T Ishibashi
  CHEMICAL PHYSICS LETTERS, 352, 1-2, 113, 119, 2002年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Vibrational frequency-shifts of H2O caused by complex formation with a molecular cation: a density functional study
  H Tachikawa; M Igarashi; T Ishibashi
  PHYSICAL CHEMISTRY CHEMICAL PHYSICS, 3, 15, 3052, 3056, 2001年, ［査読有り］
  英語, 研究論文（学術雑誌）
• 北海道大学映像教材データベース作成案
  阿部和厚; 五十嵐学
  高等教育ジャーナル─高等教育と生涯学習─, 8, 79, 84, 北海道大学, 2000年03月, ［査読有り］
  日本語
• Direct ab initio dynamics study of the photoelectron detachment processes of the H3O- anion
  M Igarashi; H Tachikawa
  INTERNATIONAL JOURNAL OF MASS SPECTROMETRY, 197, 243, 252, 2000年02月, ［査読有り］
  英語, 研究論文（学術雑誌）
• A Direct ab-initio dynamics Study on a gas phase SN2 reaction F- + CH3Cl → FCH3 + Cl-. : Dynamics of near-collinear collision
  Tachikawa H; Igarashi M
  Chem. Phys. Lett., 303, 1-2, 81, 86, 1999年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• An ab-initio MO Study on the Gas Phase SN2 reaction F- + CH3Cl → FCH3 + Cl-
  Igarashi M; Tachikawa H
  J. Mass Spectrom., 181, 151, 157, 1998年12月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Dynamics of the Ionization Processes of Benzene-H2O Clusters: A direct ab-initio Dynamics Study
  Tachikawa H; Igarashi M
  J. Phys. Chem. A, 102, 45, 8648, 8656, 1998年10月, ［査読有り］
• Collision Energy- and Spin-orbit coupling- dependence of Quenching Probability in the Electronic Energy Transfer Reaction S(1D) + CO → S(3P) + CO(v,J)
  Tachikawa H; Hamabayashi T; Igarashi M
  J. Mol. Struct. (THEOCHEM), 453, 1-3, 191, 196, 1998年10月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Formation mechanism of CCl4- anion in condensed phase a direct ab initio dynamics study
  H Tachikawa; M Igarashi; K Komaguchi
  INTERNATIONAL JOURNAL OF MASS SPECTROMETRY, 177, 1, 17, 21, 1998年08月, ［査読有り］
  英語, 研究論文（学術雑誌）

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  五十嵐学, 生体の科学, 72, 4, 321, 325, 2021年
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  伊藤朔; 五十嵐学; 阿部貴志, 日本ゲノム微生物学会年会要旨集, 14th, 2020年
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  小林由紀; 五十嵐学; 鈴木善幸, 日本進化学会大会プログラム・講演要旨集(Web), 21st, 2019年
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• ウイルス蛋白質と宿主分子の相互作用解析:計算科学の活用
  五十嵐学, CBI学会大会, 2017, 73, 2017年10月02日
  日本語
• 私達の研究(170)エボラ出血熱に対する治療法および診断法の開発
  古山若呼; 吉田玲子; 五十嵐学; 高田礼人, 化学療法の領域, 33, 5, 1098‐1105, 2017年04月25日
  日本語
• 人獣共通感染症研究における計算科学の活用
  五十嵐学, CBI学会研究講演会, 374th, 2016年
• インフルエンザウイルスHA亜型間交差反応性抗体の抗原認識機構の計算科学解析
  五十嵐学, CBI学会大会, 2015, 59, 2015年10月26日
  日本語
• インフルエンザウイルスタンパク質の計算科学的解析
  五十嵐学, 薬学雑誌, 135, 9, 1015, 1021, 2015年09月
  日本語, 書評論文,書評,文献紹介等
• インフルエンザウイルスのフコシル化α2,3シアロ糖認識機構の解析
  日尾野隆大; 岡松正敏; 五十嵐学; 五十嵐学; MCBRIDE Ryan; DE VIRES Robert; PAULSON James; 松野啓太; 松野啓太; 迫田義博; 迫田義博; 喜田宏; 喜田宏; 喜田宏, 日本獣医学会学術集会講演要旨集, 158th, 332, 2015年08月30日
  日本語
• インフルエンザウイルスのフコシル化α2,3シアロ糖認識機構の解析
  日尾野隆大; 岡松正敏; 五十嵐学; 五十嵐学; MCBRIDE Ryan; DE VIRES Robert P; PAULSON James C; 迫田義博; 迫田義博; 喜田宏; 喜田宏, 日本糖質学会年会要旨集, 34th, 173, 2015年07月01日
  日本語
• 新規マルチターゲット抗インフルエンザ阻害薬の構造活性相関研究(1)
  横田智洋; 細沢拓未; 石坪江梨花; 加藤裕也; 五十嵐学; KIRSHNER Karil N.; SRIWILAIJAROEN Nongluk; 横江弘雅; 鈴木康夫; 常盤広明; 常盤広明; 津吹政可, 日本薬学会年会要旨集(CD-ROM), 135th, 2015年
• 新規マルチターゲット抗インフルエンザ阻害剤の構造活性相関研究(2)
  加藤裕也; 細沢拓未; 石坪江梨花; 横田智洋; 五十嵐学; KIRSHNER Karil N; SRIWILAIJAROEN Nongluk; 横江弘雅; 鈴木康夫; 常盤広明; 津吹政可, 日本薬学会年会要旨集(CD-ROM), 135th, ROMBUNNO.28S-PM11, 2015年
  日本語
• 梅エキス抽出物をリードとした新規マルチターゲット抗インフルエンザ薬の合理的設計開発
  石坪江梨花; 細沢拓未; 五十嵐学; KIRSHNER Karl N; SRIWILAIJAROEN Nongluk; 横江弘雅; 津吹政可; 鈴木康夫; 常盤広明, 日本薬学会年会要旨集(CD-ROM), 135th, ROMBUNNO.28PB-AM007S, 2015年
  日本語
• インフルエンザウイルスHAタンパク質のpH依存性構造変化に関する分子シミュレーション研究
  三浦信明; 五十嵐学, 分子科学討論会講演プログラム&要旨(Web), 9th, ROMBUNNO.4P077 (WEB ONLY), 2015年
  日本語
• ニワトリのインフルエンザウイルスはフコシル化および硫酸化α2,3シアル酸糖鎖をレセプターとする
  岡松正敏; 日尾野隆大; 五十嵐学; DE VRIES Robert; 西原祥子; 高瀬明; PAULSON James C; 迫田義博; 喜田宏, 日本ウイルス学会学術集会プログラム・抄録集, 62nd, 154, 2014年10月31日
  日本語
• 豚インフルエンザウイルスの効率的なサーベイランス方法の検討
  小澤真; 松鵜彩; 米澤弘毅; 五十嵐学; 奥谷公亮; 川畑淑子; 伊藤公人; 小原恭子; 種子野章; 出口栄三郎, 日本ウイルス学会学術集会プログラム・抄録集, 62nd, 162, 2014年10月31日
  日本語
• H5N1インフルエンザウイルスに対する中和抗体を用いた受動免疫の感染防御効果
  吉田玲子; 伊藤靖; 七戸新太郎; 小笠原一誠; 日尾野隆大; 岡松正敏; 迫田義博; 喜田宏; LE Mai Quynh; 河岡義裕; 五十嵐学; 鈴木定彦; 高田礼人, 日本ウイルス学会学術集会プログラム・抄録集, 62nd, 234, 2014年10月31日
  日本語
• 遺伝子配列データをリサンプリングするウェブアプリケーションの構築
  米澤弘毅; 五十嵐学; 小原康夫; 伊藤公人, 日本ウイルス学会学術集会プログラム・抄録集, 62nd, 380, 2014年10月31日
  日本語
• 新規マルチターゲット抗インフルエンザ阻害剤の合成研究
  加藤裕也; 細沢拓未; 石坪江梨花; 五十嵐学; KIRSHNER Karl N; SRIWILAIJAROEN Nongluk; 横江弘雅; 鈴木康夫; 常盤広明; 津吹政可, 日本薬学会関東支部大会講演要旨集, 58th, 139, 2014年09月30日
  日本語
• 遺伝子配列リサンプリングのための近隣剪定法の設計とウェブアプリケーション構築
  米澤弘毅; 五十嵐学; 小原康雄; 伊藤公人, 日本遺伝学会大会プログラム・予稿集, 86th, 100, 2014年08月31日
  日本語
• ニワトリのインフルエンザウイルスはフコシル化α2,3シアル酸糖鎖をレセプターとする
  日尾野隆大; 岡松正敏; 五十嵐学; 西原祥子; 高瀬明; 迫田義博; 喜田宏, 日本糖質学会年会要旨集, 33rd, 62, 2014年07月23日
  日本語
• 第一原理計算によるムメフラールとインフルエンザウイルス表面糖タンパク質との理論的相互作用解析
  石坪江梨花; 五十嵐学; KIRSHNER Karl N; SRIWILAIJAROEN Nongluk; 細沢拓未; 横江弘雅; 津吹政可; 鈴木康夫; 常盤広明, 日本糖質学会年会要旨集, 33rd, 110, 2014年07月23日
  日本語
• めざせ!細菌学の星☆ 2014 新規炭疽ワクチン抗原の分子設計(We'll be the stars of bacteriology! 2014 De novo designed molecule to develop structure-based vaccine against anthrax)
  大西 なおみ; 武藤 芽未; 藤倉 大輔; 五十嵐 学; 東 秀明, 日本細菌学雑誌, 69, 1, 120, 120, 2014年02月
  日本細菌学会, 英語
• インフルエンザウイルス蛋白質の計算科学的解析
  五十嵐学, 日本薬学会年会要旨集(CD-ROM), 134th, ROMBUNNO.S11-4, 2014年
  日本語
• 第一原理計算を用いたインフルエンザウイルス表面糖タンパク質とマルチターゲット医薬リード天然物との高精度相互作用解析
  石坪江梨花; KIRSHNER Karl N; 五十嵐学; SRIWILAIJAROEN Nongluk; 鈴木康夫; 常盤広明, 日本ウイルス学会学術集会プログラム・抄録集, 61st, 433, 2013年10月29日
  日本語
• 計算科学手法を用いたインフルエンザウイルスヘマグルチニンと亜型間交差反応性抗体との分子間相互作用の解析
  五十嵐学; 吉田玲子; 関嶋政和; 常盤広明; 喜田宏; 伊藤公人; 高田礼人, 日本ウイルス学会学術集会プログラム・抄録集, 61st, 239, 2013年10月29日
  日本語
• ダニ媒介性フラビウイルスによる中枢神経系病態に関わるウイルス因子の同定
  好井健太朗; 寸田祐嗣; 五十嵐学; 横澤香菜; 境瑞紀; 苅和宏明; HOLBROOK Michael, 日本ウイルス学会学術集会プログラム・抄録集, 61st, 233, 2013年10月29日
  日本語
• ダニ媒介性フラビウイルスによる中枢神経系病態におけるNS5蛋白の影響の解析
  好井 健太朗; 寸田 祐嗣; 五十嵐 学; 横澤 香菜; 境 瑞紀; 苅和 宏明; Holbrook Michael; 高島 郁夫, 日本獣医学会学術集会講演要旨集, 156回, 303, 303, 2013年08月
  (公社)日本獣医学会, 日本語
• 構造ベースの抗炭疽ワクチン開発のために新規設計された分子
  大西なおみ; 武藤芽未; 藤倉大輔; 五十嵐学; 東秀明, 毒素シンポジウム予稿集, 60th, 95, 97, 2013年06月20日
  日本語
• 近隣結合法による塩基配列データセットのリサンプリングとその性能評価 (特集 「Big data と機械学習・データサイエンス」および一般)
  米澤 弘毅; 五十嵐 学; 伊藤 公人, 人工知能基本問題研究会, 88, 103, 108, 2013年01月24日
  人工知能学会, 日本語
• 近隣結合法による塩基配列データセットのリサンプリングとその性能評価
  米澤弘毅; 五十嵐学; 伊藤公人, 人工知能学会人工知能基本問題研究会資料, 88th, 103, 108, 2013年01月17日
  日本語
• 近隣剪定法によるウイルス遺伝子配列のリサンプリング
  米澤弘毅; 五十嵐学; 伊藤公人, 日本ゲノム微生物学会年会要旨集, 7th, 75, 2013年
  日本語
• フィロウイルス糖蛋白質による宿主細胞表面分子の立体的遮蔽現象の解析
  野依修; 松野啓太; 梶原将大; 中山絵里; 五十嵐学; 磯田典和; 吉田玲子; 高田礼人, 日本ウイルス学会学術集会プログラム・抄録集, 60th, 198, 2012年10月31日
  日本語
• 近隣剪定法によるウイルス遺伝子配列のリサンプリング
  米澤弘毅; 五十嵐学; 高田礼人; 伊藤公人, 日本ウイルス学会学術集会プログラム・抄録集, 60th, 321, 2012年10月31日
  日本語
• アカゲザルモデルを用いたエボラ出血熱に対する中和モノクローナル抗体の防御効果
  吉田玲子; MARZI Andrea; 宮本洋子; 石島麻理; 鈴木定彦; 五十嵐学; 中山絵里; 黒田誠; FELDMANN Heinz; 高田礼人, 日本ウイルス学会学術集会プログラム・抄録集, 60th, 199, 2012年10月31日
  日本語
• H3N2インフルエンザウイルスHAへの糖鎖付加と周辺アミノ酸残基にかかる選択圧の経詩的変化
  五十嵐学; 中尾亮; 喜田宏; 喜田宏; 高田礼人; 伊藤公人, 日本ウイルス学会学術集会プログラム・抄録集, 60th, 318, 2012年10月31日
  日本語
• 近隣剪定法 : 進化系統樹を利用した配列リサンプリングアルゴリズム (ニューロコンピューティング)
  米澤 弘毅; 五十嵐 学; 伊藤 公人, 電子情報通信学会技術研究報告 : 信学技報, 112, 108, 113, 117, 2012年06月28日
  電子情報通信学会, 日本語
• 近隣剪定法 : 進化系統樹を利用した配列リサンプリングアルゴリズム(一般,機械学習によるバイオデータマインニング,一般)
  米澤 弘毅; 五十嵐 学; 伊藤 公人, 電子情報通信学会技術研究報告. NC, ニューロコンピューティング, 112, 108, 113, 117, 2012年06月21日
  近年,インフルエンザをはじめ様々な病原体の遺伝子情報が大量に蓄積されつつある.データセットの増大に伴い,配列解析にかかる計算コストが急増している.また,疫学調査活動の差異により,データセットは調査地域や年代に関して大きなサンプリングバイアスを含む.本研究では,進化系統樹を利用してサンプリング密度の高い配列を適宜取り除くリサンプリングアルゴリズムを提案し,その性能を比較実験により評価する., 一般社団法人電子情報通信学会, 日本語
• 近隣剪定法:進化系統樹を利用した配列リサンプリングアルゴリズム
  米澤 弘毅; 五十嵐 学; 伊藤 公人, 情報処理学会研究報告. BIO, バイオ情報学, 2012, 22, 1, 5, 2012年06月21日
  近年,インフルエンザをはじめ様々な病原体の遺伝子情報が大量に蓄積されつつある.データセットの増大に伴い,配列解析にかかる計算コストが急増している.また,疫学調査活動の差異により,データセットは調査地域や年代に関して大きなサンプリングバイアスを含む.本研究では,進化系統樹を利用してサンプリング密度の高い配列を適宜取り除くリサンプリングアルゴリズムを提案し,その性能を比較実験により評価する., 一般社団法人情報処理学会, 日本語
• 計算科学的手法を用いたインフルエンザウイルス蛋白質の解析
  五十嵐学, 日本分子生物学会年会プログラム・要旨集(Web), 35th, WEB ONLY 2W3III-3, 2012年
  日本語
• 2009年のウズラ由来H7N6亜型高病原性鳥インフルエンザウイルスの感染経路の推定
  内田裕子; 金平克史; 真瀬昌司; 竹前喜洋; 渡辺千晶; 笛吹達史; 藤本佳万; 伊藤壽啓; 五十嵐学; 伊藤公人; 高田礼人; 迫田義博; 岡松正敏; 山本祐; 中村菊保; 喜田宏; 廣本靖明; 津田知幸; 西藤岳彦, 動物衛生研究成果情報, 10, 15-16, 16, 2011年09月30日
  (国研)農業・食品産業技術総合研究機構動物衛生研究部門, 日本語
• ウマMHC class Iが示すウマヘルペスウイルス1型レセプター機能の解析
  佐々木道仁; 五十嵐学; 澤洋文; 伊藤公人; 福士秀人; 木村享史, 日本獣医学会学術集会講演要旨集, 152nd, 239, 239, 2011年08月31日
  (公社)日本獣医学会, 日本語
• H3N2インフルエンザウイルスHAに付加された糖鎖は周辺エピトープを覆い隠していたか?〜糖鎖付加部位周辺アミノ酸残基の多様性変化の解析〜
  五十嵐学; 高田礼人; 喜田宏; 喜田宏; 喜田宏; 伊藤公人; 伊藤公人, 日本ウイルス学会学術集会プログラム・抄録集, 58th, 227, 2010年10月15日
  日本語
• フィロウイルス種特異抗体検出ELISA法の開発
  中山絵里; 横山文香; 宮本洋子; 岸田典子; 松野啓太; 五十嵐学; MARZI Andrea; FELDMANN Heinz; 伊藤公人; 高田礼人, 日本ウイルス学会学術集会プログラム・抄録集, 58th, 286, 2010年10月15日
  日本語
• パンデミックインフルエンザAウイルス(H1N1)ヘマグルチニンに対するモノクローナル抗体の性状解析
  吉田玲子; 苫米地大輔; 五十嵐学; 宮本洋子; 加瀬哲男; 喜田宏; 喜田宏; 喜田宏; 高田礼人, 日本ウイルス学会学術集会プログラム・抄録集, 58th, 219, 2010年10月15日
  日本語
• Cys80 of JC Virus Capsid Protein, VP1 is Essential for Intrapentamer Disulfide Bond and Pentamer Formation
  Shintaro Kobayashi; Tadaki Suzuki; Manabu Igarashi; Noriko Ohtake; Keita Nagakawa; Kimihito Ito; Kenichi Niikura; Takashi Kimura; Harumi Kasamatsu; Hirofumi Sawa, JOURNAL OF NEUROVIROLOGY, 16, 45, 46, 2010年10月
  英語, 研究発表ペーパー・要旨（国際会議）
• インフルエンザウイルスの抗原変異予測と亜型間交差感染防制
  高田礼人; 吉田玲子; 五十嵐学; 伊藤公人, 日本薬学会年会要旨集, 130th, 1, 339, 2010年03月05日
  日本語
• 愛知県でウズラから分離されたH7N6亜型鳥インフルエンザウイルスの遺伝子解析
  内田裕子; 真瀬昌司; 竹前喜洋; 廣本靖明; 五十嵐学; 伊藤公人; 高田礼人; 西藤岳彦; 津田知幸; 山口成夫, 日本ウイルス学会学術集会プログラム・抄録集, 57th, 346, 2009年10月01日
  日本語
• ホモロジーモデリング法による新型H1N1インフルエンザウイルスのヘマグルチニンの抗原構造の解析
  五十嵐学; 伊藤公人; 吉田玲子; 喜田宏; 喜田宏; 喜田宏; 高田礼人, 日本ウイルス学会学術集会プログラム・抄録集, 57th, 180, 2009年10月01日
  日本語
• インフルエンザウイルスのヘマグルチニンのMDS解析と変異予測への応用
  伊藤公人; 五十嵐学; 村上悌治; 喜田宏; 喜田宏; 高田礼人, 日本ウイルス学会学術集会プログラム・抄録集, 57th, 181, 2009年10月01日
  日本語
• マウスプリオンタンパク質ヒスチジン186周辺の銅イオン結合部位に関する構造解析
  稲波修; 渡辺康子; 五十嵐学; 伊藤公人; 堀内基広; 桑原幹典; 平岡和佳子, 日本獣医学会学術集会講演要旨集, 148th, 199, 2009年
  日本語
• インフルエンザウイルスHA遺伝子の塩基配列上に潜在する糖鎖付加ポテンシャルの解析
  五十嵐学; 伊藤公人; 喜田宏; 喜田宏; 喜田宏; 高田礼人, 日本ウイルス学会学術集会プログラム・抄録集, 56th, 144, 2008年10月01日
  日本語
• インフルエンザウイルスHA遺伝子の塩基配列上に潜在する糖鎖付加ポテンシャルの解析
  五十嵐学; 伊藤公人; 喜田宏; 喜田宏; 喜田宏; 高田礼人, 日本ウイルス学会北海道支部夏季シンポジウム講演抄録, 42nd, 12, 2008年
  日本語
• 動物インフルエンザのグローバルサーベイランスと全ての亜型ウイルスライブラリーの構築
  梶原将大; 梶原将大; 迫田義博; 迫田義博; 伊藤壽啓; 高田礼人; 岸田典子; 五十嵐学; 磯田典和; 磯田典和; 曽田公輔; 曽田公輔; 喜田宏; 喜田宏; 喜田宏, 日本ウイルス学会学術集会プログラム・抄録集, 55th, 216, 2007年10月01日
  日本語
• H5N1インフルエンザウイルスの電荷依存的なヒト型レセプター認識
  山田晋弥; 山田晋弥; 五十嵐学; 堀本泰介; 堀本泰介; 鈴木隆; 鈴木隆; 鈴木康夫; 鈴木康夫; 河岡義裕; 河岡義裕; 河岡義裕, 日本ウイルス学会学術集会プログラム・抄録集, 55th, 169, 2007年10月01日
  日本語
• 動物インフルエンザのグローバルサーベイランスと全ての亜型ウイルスライブラリーの構築
  梶原将大; 梶原将大; 迫田義博; 迫田義博; 伊藤壽啓; 高田礼人; 伊藤公人; 岸田典子; 五十嵐学; 磯田典和; 磯田典和; 曽田公輔; 曽田公輔; WEBSTER R.G; 喜田宏; 喜田宏; 喜田宏, 日本獣医学会学術集会講演要旨集, 144th, 91, 2007年08月27日
  日本語
• アイテム集合間の相関変化検出によるインフルエンザウイルス遺伝子データの解析
  谷口剛; 伊藤公人; 五十嵐学; 村上悌治; 原口誠, 人工知能学会全国大会論文集(CD−ROM), 21st, 3B8-3, 4, 2007年
  人工知能学会, 日本語
• インフルエンザウイルスの進化における共変異の変化の解析
  谷口 剛; 伊藤 公人; 五十嵐 学, 情報処理学会研究報告, 2006, 135, 185, 192, 2006年12月21日
  情報処理学会, 日本語
• インフルエンザウイルスの進化における共変異の変化の解析(セッション7)
  谷口 剛; 伊藤 公人; 五十嵐 学; 村上 悌治; 高田 礼人; 原口 誠, 情報処理学会研究報告. BIO, バイオ情報学, 2006, 135, 185, 192, 2006年12月21日
  インフルエンザウイルスにおける抗原変異の規則性を発見するために,アミノ酸残基の共変異を解析する.共変異とは,タンパク質を構成するアミノ酸残基のうち,複数の位置のアミノ酸が共に置換する現象である.従来からアミノ酸残基の共変異を解析する手法がいくつか提案されていたが,それらの手法では進化の過程における分岐や時間的関係が考慮されていなかった.そこで,これらの問題を解決するために,進化系統解析によって得られる系統樹を利用する手法を提案する.過去40年間のH3N2亜型インフルエンザウイルスのHAタンパク質を対象とし,共変異の検出を行い,その結果を示す.また,共変異は時代と共に変化するため,共変異の変化を検出するための手法を提案する., 一般社団法人情報処理学会, 日本語
• インフルエンザウイルスの進化における共変異の変化の解析(セッション7)
  谷口 剛; 伊藤 公人; 五十嵐 学; 村上 悌治; 高田 礼人; 原口 誠, 情報処理学会研究報告. MPS, 数理モデル化と問題解決研究報告, 2006, 135, 185, 192, 2006年12月21日
  インフルエンザウイルスにおける抗原変異の規則性を発見するために,アミノ酸残基の共変異を解析する.共変異とは,タンパク質を構成するアミノ酸残基のうち,複数の位置のアミノ酸が共に置換する現象である.従来からアミノ酸残基の共変異を解析する手法がいくつか提案されていたが,それらの手法では進化の過程における分岐や時間的関係が考慮されていなかった.そこで,これらの問題を解決するために,進化系統解析によって得られる系統樹を利用する手法を提案する.過去40年間のH3N2亜型インフルエンザウイルスのHAタンパク質を対象とし,共変異の検出を行い,その結果を示す.また,共変異は時代と共に変化するため,共変異の変化を検出するための手法を提案する., 一般社団法人情報処理学会, 日本語
• インフルエンザウイルス亜型間交差中和活性を有するモノクローナル抗体の解析
  吉田玲子; 五十嵐学; 喜田宏; 喜田宏; 喜田宏; 高田礼人, 日本ウイルス学会学術集会プログラム・抄録集, 54th, 347, 2006年11月01日
  日本語
• 感染症のリスクに対する認知の調査—大学生を対象として—
  増地あゆみ; 玉城英彦; 五十嵐学, 北海道心理学研究, 28, 67, 2006年09月21日
  日本語
• ペプチド‐水相互作用系の光イオン化ダイナミクス
  五十嵐学; 五十嵐学; 伊藤公人; 田池川浩人; 玉城英彦, 日本化学会北海道支部研究発表会講演要旨集, 2006, 116, 2006年01月20日
  日本語
• 札幌市立高等学校生における性の意識・実態調査 2004年
  作原ひとみ; 間島雄三; 五十嵐学; 玉城英彦, 日本公衆衛生学会総会抄録集, 64th, 690, 2005年08月15日
  日本語
• 札幌市立中学生と高校生の性意識調査の比較 2004年
  神尾知佳; 神尾知佳; 間島雄三; 五十嵐学; 玉城英彦, 日本公衆衛生学会総会抄録集, 64th, 690, 2005年08月15日
  日本語
• 札幌市立中学生における性の意識調査 2004年
  小林八重子; 間島雄三; 五十嵐学; 玉城英彦, 日本公衆衛生学会総会抄録集, 64th, 689, 2005年08月15日
  日本語
• 生物系薬学 DNAアプタマーは新たな抗インフルエンザ剤となりうるか?
  五十嵐学, ファルマシア, 41, 7, 698-699, 699, 2005年07月01日
  公益社団法人日本薬学会, 日本語
• 水和ペプチドクラスターの光イオン化ダイナミクス A direct ab‐initio trajectory study
  五十嵐学; 田地川浩人; 石橋輝雄; 玉城英彦, 日本化学会北海道支部研究発表会講演要旨集, 2005, 118, 2005年01月21日
  日本語
• 生物系薬学 DNAアプタマーは新たな抗インフルエンザ剤となりうるか?
  五十嵐学, ファルマシア, 41, 7, 2005年
• HIV検査体制の構築に関する研究 より効果的なHIVのスクリーニング検査体制を構築するための研究 北海道におけるHIV検査・相談体制に関するインターネット調査(速報)
  玉城英彦; 宇佐美香織; 広岡憲造; 間島勇三; 勝亦百合子; 五十嵐学; 工藤伸一; 今井光信, HIV検査体制の構築に関する研究 平成16年度研究報告書, 72-87, 2005年
  日本語
• 道民の性意識とジェンダーの関係 (2):インターネットモニターシステムを用いた試み
  間島勇三; 広岡憲造; 五十嵐学; 玉城英彦, 日本公衆衛生学会総会抄録集, 63rd, 821, 2004年10月15日
  日本語
• アセチルコリンエステラーゼの酵素触媒メカニズム(II)
  五十嵐学; 田地川浩人; 西平順; 石橋輝雄, 日本化学会北海道支部研究発表会講演要旨集, 2004, 125, 2004年01月21日
  日本語
• アセチルコリンエステラーゼの酵素触媒メカニズム:理論的研究
  五十嵐学; 田地川浩人; 西平順; 石橋輝雄, 分子構造総合討論会講演要旨集(CD−ROM), 2003, 4PA047, 2003年09月20日
  日本語
• 水和された生体内ペプチド鎖への光照射効果 理論モデリング
  五十嵐学; 田地川浩人; 石橋輝雄, 日本化学会北海道支部研究発表会講演要旨集, 2003, 99, 2003年01月31日
  日本語
• OH⁻による生体内S_N2反応ダイナミックス (II)
  五十嵐学; 田地川浩人; 石橋輝雄, 分子構造総合討論会講演要旨集, 2002, 709, 2002年10月01日
  日本語
• 水和されたペプチド鎖のイオン化ダイナミックス Direct ab‐initio dynamics法による理論的研究
  五十嵐学; 田地川浩人; 石橋輝雄, 化学反応討論会講演要旨集, 18th, 120, 2002年06月18日
  日本語
• 生体内S_N2反応の理論的モデル化
  五十嵐学; 田地川浩人; 石橋輝雄, 日本化学会北海道支部研究発表会講演要旨集, 2002, 124, 2002年01月20日
  日本語
• OH⁻によるS_N2反応ダイナミックス
  五十嵐学; 田地川浩人; 石橋輝雄, 分子構造総合討論会講演要旨集, 2001, 479, 2001年09月24日
  日本語
• S_N2反応に関する理論的研究
  五十嵐学; 田地川浩人; 石橋輝雄, 日本化学会北海道支部研究発表会講演要旨集, 2001, 116, 2001年01月19日
  日本語
• S_N2反応ダイナミックス A direct ab‐initio dynamics study
  五十嵐学; 田地川浩人; 石橋輝雄, 分子構造総合討論会講演要旨集, 2000, 771, 2000年09月27日
  日本語
• 北海道大学映像教材データベース作成案
  阿部 和厚; 五十嵐 学, 高等教育ジャーナル, 8, 0, 79, 84, 2000年03月
  北海道大学, 日本語
• 環状ポリシランの励起状態ダイナミックス
  山田義久; 五十嵐学; 田地川浩人, 分子構造総合討論会講演要旨集, 1998, 156, 1998年09月
  日本語
• Direct ab‐initio dynamics法によるS_N2反応の理論的研究
  五十嵐学; 田地川浩人, 分子構造総合討論会講演要旨集, 1998, 154, 1998年09月
  日本語
• S_N2反応ダイナミックス:Direct MO dynsmics法による理論的研究
  五十嵐学; 田地川浩人, 化学反応討論会講演要旨集, 14th, 32, 1998年05月
  日本語
• F⁻によるS_N2反応への溶媒効果 Direct MO dynamicsによるアプローチ
  五十嵐学; 田地川浩人; 市川恒樹, フッ素化学討論会講演要旨集, 21st, 104-105, 1997年10月
  日本語
• ベンゼン‐水クラスターのイオン化に伴う反応ダイナミックス Direct MO dynamics法による理論的研究
  五十嵐学; 田地川浩人; 市川恒樹, 分子構造総合討論会講演要旨集, 1997, 148, 1997年10月
  日本語
• アルキル芳香族カチオンラジカルからのプロトン移動速度
  小泉均; 五十嵐学; 深村真史; 市川恒樹, 放射線化学討論会講演要旨集, 40th, 139-140, 1997年
  日本語

• 大学院共通授業科目（一般科目）：自然科学・応用科学, 2024年, 修士課程, 大学院共通科目
• 生物統計学特論, 2024年, 博士後期課程, 獣医学院
• 生物統計学特論, 2024年, 博士後期課程, 国際感染症学院
• 情報科学特論, 2024年, 博士後期課程, 獣医学院
• 情報科学特論, 2024年, 博士後期課程, 国際感染症学院
• 製剤開発特論, 2024年, 博士後期課程, 国際感染症学院

• インフルエンザ研究者交流の会
• 情報計算化学生物学会
• 日本ウイルス学会

• 野外株の抗原性解析に基づくペスチウイルス感染症の次世代型ワクチン株作出基盤の確立
  科学研究費助成事業
  2025年04月01日 - 2028年03月31日
  迫田 義博; 五十嵐 学; 青木 博史
  日本学術振興会, 基盤研究(B), 北海道大学, 25K02165
• 遺伝子型に立脚した膵がん個別化医療開発基盤の創出
  科学研究費助成事業
  2023年04月 - 2027年03月
  園下 将大; 五十嵐 学; 小沼 剛; 市川 聡; 合田 圭介
  日本学術振興会, 基盤研究(B), 北海道大学, 23K27450
• フィロウイルスに広く効果を示すユニバーサル治療薬探索のための基盤技術の確立
  科学研究費助成事業
  2023年04月01日 - 2026年03月31日
  五十嵐 学; 広川 貴次; 阿部 貴志; 松野 啓太
  フィロウイルスに含まれるエボラおよびマールブルグウイルスは、ヒトに致死的な出血熱を引き起こす。その発生頻度は近年増加傾向にあり、原因ウイルス種も予測不能である。そのため、フィロウイルスに広く対応可能な治療薬開発が望まれている。しかし、感染性フィロウイルスはBSL-4施設を備えた限られた機関でしか扱えず、治療薬探索には工夫が必要である。そこで本研究では、計算機解析を活用し、ウイルス蛋白質の配列と構造情報から、フィロウイルス種に共通する創薬標的部位を同定する技術を確立する。また、同定した標的部位に対する阻害剤を設計・探索し、フィロウイルス種に広く効果を示す化合物を見つけ出す。
  ウイルスの増殖過程において、個々のウイルス蛋白質は、ウイルス蛋白質同士あるいは宿主分子と相互作用することで機能を発揮する。したがって、ウイルス蛋白質上の相互作用および機能に関連する部位（相互作用/機能部位）は、近縁ウイルス間で保存されている可能性が高い。このような部位は、フィロウイルスに幅広く効果を示す薬剤の標的になる可能性がある。本年度は、深層学習モデル Transformer を用いて、ウイルスのアミノ酸配列から蛋白質間相互作用に重要なモチーフ（Short Linear Motif: SLiM）を検出する手法の開発を行った。また、エボラおよびマールブルグウイルスの表面糖蛋白GPとエンドソーム受容体であるNiemann-Pick C1（NPC1）蛋白質との複合体構造を分子シミュレーションにより解析し、GP上のNPC1結合領域が両ウイルス共通の創薬標的部位となり得るかを検証した。
  日本学術振興会, 基盤研究(B), 北海道大学, 23K27064
• 代謝制御因子を標的とする新規膵がん治療法の開発
  次世代がん医療加速化研究事業
  2023年07月 - 2026年03月
  園下将大; 合田圭介; 小松崎民樹; 市川聡; 五十嵐学; 小沼剛
  日本医療研究開発機構(AMED), 北海道大学, 研究分担者
• フィロウイルスに広く効果を示すユニバーサル治療薬探索のための基盤技術の確立
  科学研究費助成事業 基盤研究(B)
  2023年04月 - 2026年03月
  五十嵐 学, 広川 貴次, 阿部 貴志, 松野 啓太
  日本学術振興会, 基盤研究(B), 北海道大学, 23H02371
• 宿主RNAメチルトランスフェラーゼを標的とした抗インフルエンザウイルス薬の探索
  科学研究費助成事業 国際共同研究加速基金(国際共同研究強化(B))
  2022年10月 - 2026年03月
  五十嵐 学; 松野 啓太; 日尾野 隆大
  日本学術振興会, 国際共同研究加速基金(国際共同研究強化(B)), 北海道大学, 研究代表者, 22KK0094
• 高精度立体構造予測を活用した新規ウイルスの探索：ダークマター配列への挑戦
  科学研究費助成事業 挑戦的研究(萌芽)
  2022年06月30日 - 2025年03月31日
  五十嵐 学; 堀江 真行
  日本学術振興会, 挑戦的研究(萌芽), 北海道大学, 22K19234
• 豚熱ウイルスと非定型豚ペスチウイルスの持続感染に関与するErns蛋白質の機能解析
  科学研究費助成事業 基盤研究(B)
  2022年04月01日 - 2025年03月31日
  迫田 義博; 五十嵐 学; 青木 博史
  日本学術振興会, 基盤研究(B), 北海道大学, 22H02504
• 革新的生体イメージング技術によるフラビウイルス感染動態を解析できる動物モデルの開発
  新興･再興感染症に対する革新的医薬品等開発推進研究事業
  2024年05月 - 2025年03月
  田村友和; 五十嵐学
  日本医療研究開発機構(AMED), 研究分担者
• 構造類似性から紐解くクリミア・コンゴ出血熱ウイルスの創薬標的の探索
  長崎大学感染症共同研究拠点「国際的に脅威となる一類感染症の研究及び高度 安全実験施設（BSL-4）を活用する人材の育成」補助事業 にかかる研究課題（研究分担者）
  2023年07月 - 2025年03月
  五十嵐学; 松野啓太
  長崎大学（AMED）, 北海道大学, 研究代表者
• レポーター技術を駆使したデング熱新規診断法の開発
  新興・再興感染症に対する革新的医薬品等開発推進研究事業
  2023年10月 - 2024年03月
  田村友和; 五十嵐学
  日本医療研究開発機構(AMED), 研究分担者
• 血液脳関門を透過する新規DDSによる神経向性ウイルス感染の治療法開発
  科学研究費助成事業 基盤研究(B)
  2020年04月01日 - 2023年03月31日
  好井 健太朗; 小林 進太郎; 五十嵐 学; 今内 覚
  ダニ媒介性脳炎、日本脳炎、狂犬病など神経向性の人獣共通感染症ウイルスは、脳に侵入・増殖することで重篤な神経症状を引き起こし、致死率も高い。しかし血液脳関門：BBBの存在のため、抗ウイルス分子をウイルスの増殖する脳に到達させる手法が無く、治療法が未開発であった。BBBにはトランスサイトーシスと呼ばれる物質を血流から脳内へと輸送する機構があり、近年の研究により、このBBB透過に関わる分子の機構が明らかになってきている。本研究では、このBBB透過機構に着目し、組換え抗体等の抗ウイルス分子技術と融合させることで、BBBを透過する機能を利用した抗ウイルス分子の脳内導入法を構築し、神経向性ウイルス感染に対する治療応用を試みる。
  本年度における研究では、昨年度の研究で構築した、ダニ媒介性脳炎ウイルス（TBEV）の幅広いウイルス株に対して中和効果を示すモノクローナル抗体をベースとして、BBBのトランスサイトーシスへの関与が示されている狂犬病ウイルスのG蛋白上のアミノ酸配列を融合させた組換え抗体を用いての研究を進めた。本抗体に誘導させた、狂犬病ウイルスのG蛋白上のアミノ酸配列は、神経細胞やBBBの血管内皮細胞上に発現するアセチルコリンレセプターとの結合により細胞内輸送小胞に取り込まれて、これがトランスサイトーシスに関与する事が示されている。そこで本研究ではアセチルコリンレセプターを細胞膜上に豊富に発現している神経細胞由来の培養細胞等を用いて検証した所、作製した組換え抗体分子は細胞膜表面に結合している事が示され、これはアセチルコリンレセプターを介したものである事が示唆された。さらに抗体をマウスの末梢に投与した所、マウスの脳内から抗体が検出されたことから、抗体は脳内に移行していることが示され、本研究で検証した組換え抗体分子は、脳内で増殖するウイルスに対する治療応用に有効である可能性が示唆された。
  日本学術振興会, 基盤研究(B), 長崎大学, 20H03136
• 汎フィロウイルス治療薬開発に向けたドライ-ウェット融合型研究基盤の構築
  科学研究費助成事業 基盤研究(B)
  2020年04月01日 - 2023年03月31日
  五十嵐 学; 広川 貴次; 阿部 貴志; 松野 啓太
  日本学術振興会, 基盤研究(B), 北海道大学, 20H03140
• 計算科学的手法を用いたインフルエンザウイルス中和抗体の抗原認識能の改変
  科学研究費助成事業 基盤研究(C)
  2017年04月01日 - 2023年03月31日
  五十嵐 学
  本研究では、抗体の親和性・特異性を制御するための論理的分子設計手法の確立を目指している。具体的に本研究課題では、インフルエンザウイルスの表面糖蛋白質ヘマグルチニン（HA）と中和モノクローナル抗体S139/1との複合体構造を用いて、分子動力学（MD）計算から得られる結合自由エネルギーを指標に抗体の結合能を改変し、エスケープ変異株や複数のHA亜型のウイルスを中和する抗体の設計を試みている。このような立体構造を基盤に既存抗体の親和性・特異性を改変する技術は、様々な人獣共通感染症の診断・治療研究へ幅広く応用されることが想定される。
  
  
  これまで、S139/1存在下でA/Victoria/3/75 (H3N2)（Vic株）を培養すると、HAの158番目にアミノ酸変異を持つエスケープ変異体（HA_vic158）が分離されることを明らかにした。本年度も、昨年度に引き続き、S139/1がHA_vic158に再結合できるよう、S139/1の改変を試みた。HA_vic158の158番目の残基は、S139/1のL鎖CDR3と物理的に衝突する。この衝突を回避できるL鎖CDR3を、公共データベース（PDB）に対して検索した。はじめに、PDBに登録されている抗体構造のL鎖CDR3をすべて抽出した。次に、これらをS139/1のL鎖CDR3に移植し、改変S139/1の構造モデルを計算機上で網羅的に構築した。つづいて、これらの改変S139/1とHA_vic158との親和性を結合自由エネルギー計算により評価したが、現在まで強い相互作用を示す改変S139/1は得られていない。現在、HA_vic158との衝突が小さい改変S139/1モデルを選別し、これらの改変S139/1の結合領域にアミノ酸置換を導入することで、強い相互作用を示す改変S139/1の取得を試みている。
  日本学術振興会, 基盤研究(C), 北海道大学, 17K08069
• 新規膵がん動物モデルに立脚した膵がん組み合わせ療法の開発
  次世代がん医療創生研究事業
  2020年04月 - 2022年03月
  園下 将大, 大塩 貴子, 市川 聡, 五十嵐 学
  日本医療研究開発機構(AMED), 北海道大学, 研究分担者
• フラビウイルス科ウイルスの粒子形成に関わる蛋白質の構造生物学的解析
  共同利用・共同研究拠点「微生物病共同研究拠点」事業
  2019年04月 - 2020年03月
  五十嵐学
  大阪大学微生物病研究所, 北海道大学, 研究代表者
• 立体構造情報を活用した高病原性ウイルスの蛋白質機能探索
  感染症研究革新イニシアティブ(J-PRIDE)
  2017年08月 - 2020年03月
  五十嵐 学; 松野 啓太; 高田 礼人
  日本医療研究開発機構(AMED), 北海道大学, 研究代表者
• インフルエンザウイルス亜型間交差反応性抗体の抗原認識機構の計算科学的解析と応用
  科学研究費補助金(基盤研究(C))
  2013年 - 2017年03月
  五十嵐 学
  インフルエンザウイルスのHA蛋白質は16種類（H1-H16）の亜型に分類される。我々はこれまで、H1、H2、H3、H13およびH16亜型のウイルスに対して中和活性を示すモノクローナル抗体S139/1の作出に成功した。本研究では、計算科学的手法により、S139/1の分子認識機構を詳細に解析した。その結果、S139/1が中和活性を示す株において、S139/1と強く結合するHA上10箇所の残基位置を同定した。また、水素結合解析から、156、158、193番目の残基位置が特に重要であることが明らかになった。実際、これらの位置はS139/1のエスケープ変異実験で観測される変異位置と一致していた。
  文部科学省, 基盤研究(C), 北海道大学, 研究代表者, 競争的資金, 25450417
• インフルエンザウイルスヘマグルチニン亜型間交差反応性抗体とエピトープに関する研究
  科学研究費助成事業 基盤研究(B)
  2012年04月 - 2017年03月
  高田 礼人; 伊藤 公人; 五十嵐 学; 吉田 玲子; 村松 美笑子; 宮本 洋子
  インフルエンザAウイルスのヘマグルチニン(HA)亜型間交差感染防御免疫における抗体の役割を、新たな抗ウイルス活性（ウイルス出芽阻害）を測定する手法によって明らかにした。特に、HA分子上の同じエピトープを認識するモノクローナルIgGおよびIgA抗体の比較によるIgAの優位性の実証に至った。また、構造情報を基にした分子間相互作用シミュレーション技術と組換え抗体作出技術を用いて、抗体の特異性を改変する技術の開発を試みた。
  日本学術振興会, 基盤研究(B), 北海道大学, 連携研究者, 24390110
• 文字列集合からの逐次データ同化によるインフルエンザウイルスの抗原変異予測
  科学研究費助成事業 基盤研究(B)
  2013年04月 - 2016年03月
  伊藤 公人; 高田 礼人; 五十嵐 学
  インフルエンザの予防にはワクチン接種が有効であるが，人の免疫圧による選択淘汰を受けてウイルスの遺伝子が変異し続けるため，ワクチン株を頻繁に更新しなければならない。そこで，本研究では，ワクチン株を先回りして準備するために，文字列の集合に対する逐次データ同化により，ウイルス遺伝子配列の実データから，近い将来におこるウイルス遺伝子上の変異を予測する手法を研究した。その結果，人の集団免疫と感染およびウイルスの遺伝子変異の過程を表すモデルが構築され，文字列集合からの逐次データ同化により，インフルエンザウイルスの抗原変異を予測する研究基盤を構築した。
  日本学術振興会, 基盤研究(B), 北海道大学, 連携研究者, 25280080
• フィロウイルスの粒子形成過程を阻害する抗体の研究
  科学研究費助成事業 挑戦的萌芽研究
  2012年04月01日 - 2014年03月31日
  高田 礼人; 伊藤 公人; 五十嵐 学
  マールブルグウイルス (MARV) の表面糖蛋白質(GP) 特異的モノクローナル抗体を作出し、ウイルス出芽阻害活性の有無を解析した。その結果、通常の中和活性は持たない抗体の中に、MARV粒子の感染細胞からの出芽・放出を顕著に抑制する抗体が存在することが明らかとなった。これらの抗体存在下で増殖可能なエスケープ変異体を選択し、GPに導入されたアミノ酸変異を調べた結果、ムチン様領域の大規模な欠損またはfurin開裂部位の点変異が認められた。以上の結果より、抗体によるMARV感染抑制の新規メカニズムとMARVのユニークな免疫逃避メカニズムが明らかとなった。
  日本学術振興会, 挑戦的萌芽研究, 北海道大学, 24658252
• インフルエンザウイルスと亜型間交差反応性抗体の相互作用解析と薬剤設計への応用
  研究助成（奨励）
  2013年
  五十嵐 学
  公益財団法人 秋山記念生命科学振興財団, 研究代表者, 競争的資金
• インフルエンザウイルスと抗体の相互作用の解析と抗原変異予測への応用
  科学研究費補助金(若手研究(B))
  2011年 - 2012年
  五十嵐 学
  インフルエンザの流行を効率よく制御するためには、抗原変異の機序を理解し、予測することが必要である。本研究では、インフルエンザウイルスの主要抗原であるヘマグルチニン（HA）とそのモノクローナル抗体（mAb）に焦点をあて、ウイルスがmAbからエスケープする際に起こるHA上のアミノ酸置換の特徴を明らかにすることを目的とした。具体的には、アミノ酸置換に伴うHA-mAb複合体の相互作用変化、およびHAの機能や構造安定性への影響を分子シミュレーション等の計算科学的手法により解析し、実際にエスケープ変異株で観測されるアミノ酸と比較した。
  文部科学省, 若手研究(B), 北海道大学, 研究代表者, 競争的資金, 23780305
• インフルエンザウイルスの抗原変異に伴う立体構造変化の解析
  科学研究費補助金(若手研究(B))
  2009年 - 2010年
  五十嵐 学
  インフルエンザの流行を効率よく制御するためには、抗原変異の機序を理解し、予測することが必要である。本研究では、インフルエンザウイルスの主要抗原であるヘマグルチニン(HA)の立体構造に焦点をあて、構造バイオインフォマティクス的手法により、抗原変異に伴うHAの抗原構造の変遷を解析した。また結果に基づき、パンデミック2009(H1N1)ウイルスの抗原変異に伴う今後のアミノ酸置換を予測した。
  文部科学省, 若手研究(B), 北海道大学, 研究代表者, 競争的資金, 21780272
• 計算科学的手法を用いたインフルエンザウイルスヘマグルチニンの構造変化解析
  科学研究費補助金(若手研究(B))
  2007年 - 2008年
  五十嵐 学
  ヒトに馴化したインフルエンザウイルスは、抗原性を毎年少しずつ変化させて、ヒトの免疫機構を巧みに回避し、流行を繰り返す。もし、この変異の過程を予測することが出来れば、インフルエンザを先回りして制御することが出来る。本研究では、計算科学的手法を用いてヒトインフルエンザウイルスの抗原変異に伴う抗原構造の変遷を解析し、将来いずれかのHA 亜型の鳥インフルエンザウイルスがヒトの新型インフルエンザウイルスとして出現した場合の予測方法を検討した。
  文部科学省, 若手研究(B), 北海道大学, 研究代表者, 競争的資金, 19780223
• 量子動力学シミュレーションによる神経伝達物質とレセプターとの相互作用の解明
  2001年 - 2003年
  五十嵐学
  文部科学省: 科学研究費補助金(特別研究員奨励費), 研究代表者, 競争的資金

• 抗インフルエンザウイルス用組成物、医薬、飲食品、サプリメント、農薬、飼料および化粧料
  特許権, 五十嵐学; 加藤博己; 塚本雄太, 国立大学法人北海道大学
  PCT/JP2023/036277, 2023年10月04日
• 免疫誘導剤
  特許権, 増田 健一; 齊藤 隆; 石井 保之; 高田 礼人; 五十嵐 学; 丸山 隼輝; 齋藤 祐介; 奈良 拓也, 国立研究開発法人理化学研究所, 動物アレルギー検査株式会社, 国立大学法人北海道大学
  特願2016-216753, 2016年11月04日
  特開2018-070571, 2018年05月10日
  201803010563100282
• エボラウイルスワクチン
  特許権, 増田 健一; 齊藤 隆; 石井 保之; 高田 礼人; 五十嵐 学; 丸山 隼輝; 齋藤 祐介; 奈良 拓也, 国立研究開発法人理化学研究所, 動物アレルギー検査株式会社, 国立大学法人北海道大学
  特願2016-188897, 2016年09月27日
  特開2018-052837, 2018年04月05日
  201803015653821541
• Ｈ５亜型インフルエンザウイルスに対する抗体およびその利用
  特許権, 樋口恵; 鈴木定彦; 高田礼人; 喜田宏; 吉田玲子; 五十嵐学; 宮本洋子
  特願2009-275367