研究者情報

マスター

アカウント（マスター）

• 氏名

  田畑　耕史郎(タバタ　コウシロウ), タバタ　コウシロウ

所属（マスター）

• 創成研究機構ワクチン研究開発拠点

所属（マスター）

• 創成研究機構ワクチン研究開発拠点

researchmap

プロフィール情報

所属

• 北海道大学, 創成研究機構ワクチン研究開発拠点, 特任助教

学位

• 博士（獣医学）（2023年03月 北海道大学）
• 修士（薬科学）（2019年03月 東京理科大学）

プロフィール情報

• 姓

  田畑, タバタ

• 名

  耕史郎, コウシロウ

• ID各種

  202301013316524802

所属

• 北海道大学, 創成研究機構ワクチン研究開発拠点, 特任助教

業績リスト

研究分野

• ライフサイエンス / ウイルス学 / ワクチン学

経歴

• 2023年04月 - 現在 北海道大学 ワクチン研究開発拠点 特任助教
• 2020年04月 - 2023年03月 日本学術振興会 特別研究員（DC1）

学歴

• 2019年04月 - 2023年03月   北海道大学   大学院国際感染症学院   博士課程
• 2017年04月 - 2019年03月   東京理科大学   薬学研究科   修士課程
• 2013年04月 - 2017年03月   東京理科大学   薬学部   生命創薬科学科

受賞

• 2023年12月 日本抗体学会 ポスター発表優秀賞
  

論文

• A wide distribution of Beiji nairoviruses and related viruses in Ixodes ticks in Japan

  Mai Kishimoto, Yukari Itakura, Koshiro Tabata, Rika Komagome, Hiroki Yamaguchi, Kohei Ogasawara, Ryo Nakao, Yongjin Qiu, Kozue Sato, Hiroki Kawabata, Masahiro Kajihara, Naota Monma, Junji Seto, Asako Shigeno, Masayuki Horie, Michihito Sasaki, William W. Hall, Hirofumi Sawa, Yasuko Orba, Keita Matsuno

  Ticks and Tick-borne Diseases 2024年11月
• Increased production of orthoflavivirus single-round infectious particles produced in mammalian cells at a suboptimal culture temperature of 28°C

  Koshiro Tabata, Shintaro Kobayashi, Yukari Itakura, Gabriel Gonzalez, Chilekwa F. Kabamba, Shinji Saito, Michihito Sasaki, William W. Hall, Hirofumi Sawa, Yasuko Orba

  Journal of Virological Methods 329 115007 - 115007 2024年09月
• Establishment of a lethal mouse model of emerging tick-borne orthonairovirus infections.

  Takuma Ariizumi, Koshiro Tabata, Yukari Itakura, Hiroko Kobayashi, William W Hall, Michihito Sasaki, Hirofumi Sawa, Keita Matsuno, Yasuko Orba

  PLoS pathogens 20 3 e1012101  2024年03月 

  Emerging and reemerging tick-borne virus infections caused by orthonairoviruses (family Nairoviridae), which are genetically distinct from Crimean-Congo hemorrhagic fever virus, have been recently reported in East Asia. Here, we have established a mouse infection model using type-I/II interferon receptor-knockout mice (AG129 mice) both for a better understanding of the pathogenesis of these infections and validation of antiviral agents using Yezo virus (YEZV), a novel orthonairovirus causing febrile illnesses associated with tick bites in Japan and China. YEZV-inoculated AG129 mice developed hepatitis with body weight loss and died by 6 days post infection. Blood biochemistry tests showed elevated liver enzyme levels, similar to YEZV-infected human patients. AG129 mice treated with favipiravir survived lethal YEZV infection, demonstrating the anti-YEZV effect of this drug. The present mouse model will help us better understand the pathogenicity of the emerging tick-borne orthonairoviruses and the development of specific antiviral agents for their treatment.
• Combination therapy with oral antiviral and anti-inflammatory drugs improves the efficacy of delayed treatment in a COVID-19 hamster model.

  Michihito Sasaki, Tatsuki Sugi, Shun Iida, Yuichiro Hirata, Shinji Kusakabe, Kei Konishi, Yukari Itakura, Koshiro Tabata, Mai Kishimoto, Hiroko Kobayashi, Takuma Ariizumi, Kittiya Intaruck, Haruaki Nobori, Shinsuke Toba, Akihiko Sato, Keita Matsuno, Junya Yamagishi, Tadaki Suzuki, William W Hall, Yasuko Orba, Hirofumi Sawa

  EBioMedicine 99 104950 - 104950 2023年12月29日 

  BACKGROUND: Pulmonary infection with SARS-CoV-2 stimulates host immune responses and can also result in the progression of dysregulated and critical inflammation. Throughout the pandemic, the management and treatment of COVID-19 has been continuously updated with a range of antiviral drugs and immunomodulators. Monotherapy with oral antivirals has proven to be effective in the treatment of COVID-19. However, treatment should be initiated in the early stages of infection to ensure beneficial therapeutic outcomes, and there is still room for further consideration on therapeutic strategies using antivirals. METHODS: We studied the therapeutic effects of monotherapy with the oral antiviral ensitrelvir or the anti-inflammatory corticosteroid methylprednisolone and combination therapy with ensitrelvir and methylprednisolone in a delayed dosing model of hamsters infected with SARS-CoV-2. FINDINGS: Combination therapy with ensitrelvir and methylprednisolone improved respiratory conditions and reduced the development of pneumonia in hamsters even when the treatment was started after 2 days post-infection. The combination therapy led to a differential histological and transcriptomic pattern in comparison to either of the monotherapies, with reduced lung damage and down-regulation of expression of genes involved in the inflammatory response. Furthermore, we found that the combination treatment is effective in case of infection with either the highly pathogenic delta or circulating omicron variants. INTERPRETATION: Our results demonstrate the advantage of combination therapy with antiviral and corticosteroid drugs in COVID-19 treatment from the perspective of lung pathology and host inflammatory responses. FUNDING: Funding bodies are described in the Acknowledgments section.
• 2-thiouridine is a broad-spectrum antiviral nucleoside analogue against positive-strand RNA viruses.

  Kentaro Uemura, Haruaki Nobori, Akihiko Sato, Shinsuke Toba, Shinji Kusakabe, Michihito Sasaki, Koshiro Tabata, Keita Matsuno, Naoyoshi Maeda, Shiori Ito, Mayu Tanaka, Yuki Anraku, Shunsuke Kita, Mayumi Ishii, Kayoko Kanamitsu, Yasuko Orba, Yoshiharu Matsuura, William W Hall, Hirofumi Sawa, Hiroshi Kida, Akira Matsuda, Katsumi Maenaka

  Proceedings of the National Academy of Sciences of the United States of America 120 42 e2304139120  2023年10月17日 

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are causing significant morbidity and mortality worldwide. Furthermore, over 1 million cases of newly emerging or re-emerging viral infections, specifically dengue virus (DENV), are known to occur annually. Because no virus-specific and fully effective treatments against these or many other viruses have been approved, there is an urgent need for novel, effective therapeutic agents. Here, we identified 2-thiouridine (s2U) as a broad-spectrum antiviral ribonucleoside analogue that exhibited antiviral activity against several positive-sense single-stranded RNA (ssRNA+) viruses, such as DENV, SARS-CoV-2, and its variants of concern, including the currently circulating Omicron subvariants. s2U inhibits RNA synthesis catalyzed by viral RNA-dependent RNA polymerase, thereby reducing viral RNA replication, which improved the survival rate of mice infected with DENV2 or SARS-CoV-2 in our animal models. Our findings demonstrate that s2U is a potential broad-spectrum antiviral agent not only against DENV and SARS-CoV-2 but other ssRNA+ viruses.
• 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 2023年10月13日 

  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.
• Impact of imprinted immunity induced by mRNA vaccination in an experimental animal model.

  Shigeru Fujita, Keiya Uriu, Lin Pan, Naganori Nao, Koshiro Tabata, Mai Kishimoto, Yukari Itakura, Hirofumi Sawa, Izumi Kida, Tomokazu Tamura, Takasuke Fukuhara, Jumpei Ito, Keita Matsuno, Kei Sato

  The Journal of infectious diseases 2023年06月27日 

  The emergence of SARS-CoV-2 Omicron variants has led to concerns that ancestral SARS-CoV-2-based vaccines may not be effective against newly emerging Omicron subvariants. The concept of "imprinted immunity" suggests that individuals vaccinated with ancestral virus-based vaccines may not develop effective immunity against newly emerging Omicron subvariants, such as BQ.1.1 and XBB.1. Here, we investigated this possibility using hamsters. While natural infection induced effective antiviral immunity, breakthrough infections in hamsters with BQ.1.1 and XBB.1 Omicron subvariants after receiving the 3-dose mRNA-LNP vaccine resulted in only faintly induced humoral immunity, supporting the possibility of imprinted immunity.
• Morphogenesis of Bullet-Shaped Rabies Virus Particles Regulated by TSG101

  Yukari Itakura, Koshiro Tabata, Takeshi Saito, Kittiya Intaruck, Nijiho Kawaguchi, Mai Kishimoto, Shiho Torii, Shintaro Kobayashi, Naoto Ito, Michiko Harada, Satoshi Inoue, Ken Maeda, Ayato Takada, William W. Hall, Yasuko Orba, Hirofumi Sawa, Michihito Sasaki

  Journal of Virology 97 5 e0043823  2023年04月12日 

  Enveloped viruses bud from cells with the host lipid bilayer. Generally, the membrane modulation and abscission are mediated by host ESCRT complexes.
• Isolation and Characterization of Distinct Rotavirus A in Bat and Rodent Hosts

  Mai Kishimoto, Masahiro Kajihara, Koshiro Tabata, Yukari Itakura, Shinsuke Toba, Seiya Ozono, Yuko Sato, Tadaki Suzuki, Naoto Ito, Katendi Changula, Yongjin Qiu, Akina Mori-Kajihara, Yoshiki Eto, Hayato Harima, Daniel Mwizabi, Bernard M. Hang’ombe, William W. Hall, Ayato Takada, Yasuko Orba, Hirofumi Sawa, Michihito Sasaki

  Journal of Virology 97 1 2023年01月31日 

  Recent advances in nucleotide sequence detection methods have enabled the detection of RVA genomes from various animals. These studies have discovered multiple divergent RVAs and have resulted in proposals for the genetic classification of novel genotypes.
• S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters

  Michihito Sasaki, Koshiro Tabata, Mai Kishimoto, Yukari Itakura, Hiroko Kobayashi, Takuma Ariizumi, Kentaro Uemura, Shinsuke Toba, Shinji Kusakabe, Yuki Maruyama, Shun Iida, Noriko Nakajima, Tadaki Suzuki, Shinpei Yoshida, Haruaki Nobori, Takao Sanaki, Teruhisa Kato, Takao Shishido, William W. Hall, Yasuko Orba, Akihiko Sato, Hirofumi Sawa

  Science Translational Medicine 15 679 2023年01月18日 

  In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Oral antiviral medication demands not only high antiviral activity but also target specificity, favorable oral bioavailability, and high metabolic stability. Although a large number of compounds have been identified as potential inhibitors of SARS-CoV-2 infection in vitro, few have proven to be effective in vivo. Here, we show that oral administration of S-217622 (ensitrelvir), an inhibitor of SARS-CoV-2 main protease (M pro ; also known as 3C-like protease), decreases viral load and ameliorates disease severity in SARS-CoV-2–infected hamsters. S-217622 inhibited viral proliferation at low nanomolar to submicromolar concentrations in cells. Oral administration of S-217622 demonstrated favorable pharmacokinetic properties and accelerated recovery from acute SARS-CoV-2 infection in hamster recipients. Moreover, S-217622 exerted antiviral activity against SARS-CoV-2 variants of concern, including the highly pathogenic Delta variant and the recently emerged Omicron BA.5 and BA.2.75 variants. Overall, our study provides evidence that S-217622, an antiviral agent that is under evaluation in a phase 3 clinical trial (clinical trial registration no. jRCT2031210350), has remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.
• Virological characteristics of the SARS-CoV-2 Omicron BA.2.75 variant

  Akatsuki Saito, Tomokazu Tamura, Jiri Zahradnik, Sayaka Deguchi, Koshiro Tabata, Yuki Anraku, Izumi Kimura, Jumpei Ito, Daichi Yamasoba, Hesham Nasser, Mako Toyoda, Kayoko Nagata, Keiya Uriu, Yusuke Kosugi, Shigeru Fujita, Maya Shofa, Mst Monira Begum, Ryo Shimizu, Yoshitaka Oda, Rigel Suzuki, Hayato Ito, Naganori Nao, Lei Wang, Masumi Tsuda, Kumiko Yoshimatsu, Jin Kuramochi, Shunsuke Kita, Kaori Sasaki-Tabata, Hideo Fukuhara, Katsumi Maenaka, Yuki Yamamoto, Tetsuharu Nagamoto, Hiroyuki Asakura, Mami Nagashima, Kenji Sadamasu, Kazuhisa Yoshimura, Takamasa Ueno, Gideon Schreiber, Akifumi Takaori-Kondo, Kotaro Shirakawa, Hirofumi Sawa, Takashi Irie, Takao Hashiguchi, Kazuo Takayama, Keita Matsuno, Shinya Tanaka, Terumasa Ikeda, Takasuke Fukuhara, Kei Sato

  CELL HOST & MICROBE 30 9 1540 - + 2022年09月 

  The SARS-CoV-2 Omicron BA.2.75 variant emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically distinct from BA.5, the currently predominant BA.2 descendant. Here, we show that BA.2.75 has a greater effective reproduction number and different immunogenicity profile than BA.5. We determined the sensitivity of BA.2.75 to vaccinee and convalescent sera as well as a panel of clinically available antiviral drugs and antibodies. Antiviral drugs largely retained potency, but antibody sensitivity varied depending on several key BA.2.75-specific substitutions. The BA.2.75 spike exhibited a profoundly higher affinity for its human receptor, ACE2. Additionally, the fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were greater than those of BA.2. Our multilevel investigations suggest that BA.2.75 acquired virological properties independent of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5.
• Serological characterization of lineage II insect-specific flaviviruses compared with pathogenic mosquito-borne flaviviruses

  Koshiro Tabata, Yukari Itakura, Shinsuke Toba, Kentaro Uemura, Mai Kishimoto, Michihito Sasaki, Jessica J. Harrison, Akihiko Sato, William W. Hall, Roy A. Hall, Hirofumi Sawa, Yasuko Orba

  Biochemical and Biophysical Research Communications 616 115 - 121 2022年08月06日 

  The genus Flavivirus includes pathogenic tick- and mosquito-borne flaviviruses as well as non-pathogenic insect-specific flaviviruses (ISFVs). Phylogenetic analysis based on whole amino acid sequences has indicated that lineage II ISFVs have similarities to pathogenic flaviviruses. In this study, we used reactive analysis with immune serum against Psorophora flavivirus (PSFV) as a lineage IIa ISFV, and Barkeji virus (BJV) as a lineage IIb ISFV, to evaluate the antigenic similarity among lineage IIa and IIb ISFVs, and pathogenic mosquito-borne flaviviruses (MBFVs). Binding and antibody-dependent enhancement assays showed that anti-PSFV sera had broad cross-reactivity with MBFV antigens, while anti-BJV sera had low cross-reactivity. Both of the lineage II ISFV antisera were rarely observed to neutralize MBFVs. These results suggest that lineage IIa ISFV PSFV has more antigenic similarity to MBFVs than lineage IIb ISFV BJV.
• A high-affinity aptamer with base-appended base-modified DNA bound to isolated authentic SARS-CoV-2 strains wild-type and B.1.617.2 (delta variant)

  hirotaka minagawa, Hirofumi Sawa, Tomoko Fujita, Shintaro Kato, Asumi Inaguma, Miwako Hirose, Yasuko Orba, Michihito Sasaki, Koshiro Tabata, Naoki Nomura, Masashi Shingai, Yasuhiko Suzuki, Katsunori Horii

  Biochemical and Biophysical Research Communications 614 207 - 212 2022年07月
• Glu333 in rabies virus glycoprotein is involved in virus attenuation through astrocyte infection and interferon responses

  Yukari Itakura, Koshiro Tabata, Kohei Morimoto, Naoto Ito, Herman M. Chambaro, Ryota Eguchi, Ken-ichi Otsuguro, William W. Hall, Yasuko Orba, Hirofumi Sawa, Michihito Sasaki

  iScience 25 4 104122 - 104122 2022年04月
• Air-liquid interphase culture confers SARS-CoV-2 susceptibility to A549 alveolar epithelial cells

  Michihito Sasaki, Mai Kishimoto, Yukari Itakura, Koshiro Tabata, Kittiya Intaruck, Kentaro Uemura, Shinsuke Toba, Takao Sanaki, Akihiko Sato, William W. Hall, Yasuko Orba, Hirofumi Sawa

  Biochemical and Biophysical Research Communications 577 146 - 151 2021年11月05日 

  The human lung cell A549 is susceptible to infection with a number of respiratory viruses. However, A549 cells are resistant to Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infection in conventional submerged culture, and this would appear to be due to low expression levels of the SARS-CoV-2 entry receptor: angiotensin-converting enzyme-2 (ACE2). Here, we examined SARS-CoV-2 susceptibility to A549 cells after adaptation to air-liquid interface (ALI) culture. A549 cells in ALI culture yielded a layer of mucus on their apical surface, exhibited decreased expression levels of the proliferation marker KI-67 and intriguingly became susceptible to SARS-CoV-2 infection. We found that A549 cells increased the endogenous expression levels of ACE2 and TMPRSS2 following adaptation to ALI culture conditions. Camostat, a TMPRSS2 inhibitor, reduced SARS-CoV-2 infection in ALI-cultured A549 cells. These findings indicate that ALI culture switches the phenotype of A549 cells from resistance to susceptibility to SARS-CoV-2 infection through upregulation of ACE2 and TMPRSS2.
• Structure-Guided Creation of an Anti-HA Stalk Antibody F11 Derivative That Neutralizes Both F11-Sensitive and -Resistant Influenza A(H1N1)pdm09 Viruses

  Osamu Kotani, Yasushi Suzuki, Shinji Saito, Akira Ainai, Akira Ueno, Takuya Hemmi, Kaori Sano, Koshiro Tabata, Masaru Yokoyama, Tadaki Suzuki, Hideki Hasegawa, Hironori Sato

  Viruses 13 9 1733 - 1733 2021年08月31日 

  The stalk domain of influenza virus envelope glycoprotein hemagglutinin (HA) constitutes the axis connecting the head and transmembrane domains, and plays pivotal roles in conformational rearrangements of HA for virus infection. Here we characterized molecular interactions between the anti-HA stalk neutralization antibody F11 and influenza A(H1N1)pdm09 HA to understand the structural basis of the actions and modifications of this antibody. In silico structural analyses using a model of the trimeric HA ectodomain indicated that the F11 Fab fragment has physicochemical properties, allowing it to crosslink two HA monomers by binding to a region near the proteolytic cleavage site of the stalk domain. Interestingly, the F11 binding allosterically caused a marked suppression of the structural dynamics of the HA cleavage loop and flanking regions. Structure-guided mutagenesis of the F11 antibody revealed a critical residue in the F11 light chain for the F11-mediated neutralization. Finally, the mutagenesis led to identification of a unique F11 derivative that can neutralize both F11-sensitive and F11-resistant A(H1N1)pdm09 viruses. These results raise the possibility that F11 sterically and physically disturbs proteolytic cleavage of HA for the ordered conformational rearrangements and suggest that in silico guiding experiments can be useful to create anti-HA stalk antibodies with new phenotypes.
• SARS-CoV-2 Bearing a Mutation at the S1/S2 Cleavage Site Exhibits Attenuated Virulence and Confers Protective Immunity

  Michihito Sasaki, Shinsuke Toba, Yukari Itakura, Herman M. Chambaro, Mai Kishimoto, Koshiro Tabata, Kittiya Intaruck, Kentaro Uemura, Takao Sanaki, Akihiko Sato, William W. Hall, Yasuko Orba, Hirofumi Sawa

  mBio 12 4 e0141521  2021年08月31日 

  SARS-CoV-2 uses its spike protein to enter target cells. The spike protein is cleaved by a host protease, and this event facilitates viral entry and broadens cell tropism.
• Host Serine Proteases TMPRSS2 and TMPRSS11D Mediate Proteolytic Activation and Trypsin-Independent Infection in Group A Rotaviruses

  Michihito Sasaki, Yukari Itakura, Mai Kishimoto, Koshiro Tabata, Kentaro Uemura, Naoto Ito, Makoto Sugiyama, Christida E. Wastika, Yasuko Orba, Hirofumi Sawa

  Journal of Virology 95 11 2021年05月10日 

  Proteolytic cleavage of the viral VP4 protein is essential for virion maturation and infectivity in group A rotaviruses (RVAs). In cell culture, RVAs are propagated in culture medium supplemented with the exogenous protease trypsin, which cleaves VP4 and induces the maturation of progeny RVA virions.
• Development of a highly specific serodiagnostic ELISA for West Nile virus infection using subviral particles

  Keisuke Maezono, Shintaro Kobayashi, Koshiro Tabata, Kentaro Yoshii, Hiroaki Kariwa

  Scientific Reports 11 1 2021年04月28日 

  AbstractWest Nile virus (WNV), a member of the Japanese encephalitis virus (JEV) serocomplex group, causes lethal encephalitis in humans and horses. Because serodiagnosis of WNV and JEV is hampered by cross-reactivity, the development of a simple, secure, and WNV-specific serodiagnostic system is required. The coexpression of prM protein and E protein leads to the secretion of subviral particles (SPs). Deletion of the C-terminal region of E protein is reported to affect the production of SPs by some flaviviruses. However, the influence of such a deletion on the properties and antigenicity of WNV E protein is unclear. We analyzed the properties of full-length E protein and E proteins lacking the C-terminal region as novel serodiagnostics for WNV infection. Deletion of the C-terminal region of E protein suppressed the formation of SPs but did not affect the production of E protein. The sensitivity of an enzyme-linked immunosorbent assay (ELISA) using the full-length E protein was higher than that using the truncated E proteins. Furthermore, in the ELISA using full-length E protein, there was little cross-reactivity with anti-JEV antibodies, and the sensitivity was similar to that of the neutralization test.
• An influenza HA stalk reactive polymeric IgA antibody exhibits anti-viral function regulated by binary interaction between HA and the antibody

  Kaori Sano, Shinji Saito, Tadaki Suzuki, Osamu Kotani, Akira Ainai, Elly van Riet, Koshiro Tabata, Kumpei Saito, Yoshimasa Takahashi, Masaru Yokoyama, Hironori Sato, Takahiro Maruno, Kaede Usami, Susumu Uchiyama, Kiyoko Ogawa-Goto, Hideki Hasegawa

  PLOS ONE 16 1 2021年01月07日 

  IgA antibodies, which are secreted onto the mucosal surface as secretory IgA antibodies (SIgAs), play an important role in preventing influenza virus infection. A recent study reported that anti-hemagglutinin (HA) head-targeting antibodies increase anti-viral functions such as hemagglutination inhibition (HI) and virus neutralization (NT), in addition to HA binding activity (reactivity) via IgA polymerization. However, the functional properties of anti-viral IgA antibodies with mechanisms of action distinct from those of anti-HA head-targeting antibodies remain elusive. Here, we characterized the functional properties of IgG, monomeric IgA, and polymeric IgA anti-HA stalk-binding clones F11 and FI6, and B12 (a low affinity anti-HA stalk clone), as well as Fab-deficient (ΔFab) IgA antibodies. We found that IgA polymerization impacts the functional properties of anti-HA stalk antibodies. Unlike anti-HA head antibodies, the anti-viral functions of anti-HA stalk antibodies were not simply enhanced by IgA polymerization. The data suggest that two modes of binding (Fab paratope-mediated binding to the HA stalk, and IgA Fc glycan-mediated binding to the HA receptor binding site (RBS)) occur during interaction between anti-stalk HA IgA antibodies and HA. In situations where Fab paratope-mediated binding to the HA stalk exceeded IgA Fc glycan-mediated binding to HA RBS, IgA polymerization increased anti-viral functions. By contrast, when IgA Fc glycan-mediated binding to the HA RBS was dominant, anti-viral activity will fall upon IgA polymerization. In summary, the results suggest that coordination between these two independent binding modules determines whether IgA polymerization has a negative or positive effect on the anti-viral functions of anti-HA stalk IgA antibodies.
• Stereotyped B-cell response that counteracts antigenic variation of influenza viruses

  Keisuke Tonouchi, Yu Adachi, Saya Moriyama, Kaori Sano, Koshiro Tabata, Keigo Ide, Haruko Takeyama, Tadaki Suzuki, Yoshimasa Takahashi

  International Immunology 32 9 613 - 621 2020年09月08日 

  Abstract Influenza A subtypes are categorized into group 1 and group 2 based on the hemagglutinin (HA) sequence. Owing to the phylogenetic distance of HAs in different groups, antibodies that bind multiple HA subtypes across different groups are extremely rare. In this study, we demonstrated that an immunization with acid-treated HA antigen elicits germinal center (GC) B cells that bind multiple HA subtypes in both group 1 and group 2. The cross-group GC B cells utilized mostly one VH gene (1S56) and exhibited a sign of clonal evolution within GCs. The 1S56-lineage IgGs derived from GC B cells were able to bind to HA protein on the infected cell surface but not to the native form of HA protein, suggesting the cryptic nature of the 1S56 epitope and its exposure in infected cells. Finally, the 1S56-lineage IgGs provided protection against lethal infection in an Fc-dependent manner, independent of the virus-neutralizing activity. Thus, we identified 1S56-lineage antibodies as a unique stereotype for achieving cross-group influenza specificity. The antigens exposing the 1S56 epitope may be good candidates for broadly protective immunogens.
• Host ESCRT factors are recruited during chikungunya virus infection and are required for the intracellular viral replication cycle

  Shiho Torii, Yasuko Orba, Michihito Sasaki, Koshiro Tabata, Yuji Wada, Michael Carr, Jody Hobson-Peters, Roy Hall, Ayato Takada, Takasuke Fukuhara, Yoshiharu Matsuura, William W. Hall, Hirofumi Sawa

  Journal of Biological Chemistry 295 23 7941 - 7957 2020年06月
• IgA tetramerization improves target breadth but not peak potency of functionality of anti-influenza virus broadly neutralizing antibody

  Shinji Saito, Kaori Sano, Tadaki Suzuki, Akira Ainai, Yuki Taga, Tomonori Ueno, Koshiro Tabata, Kumpei Saito, Yuji Wada, Yuki Ohara, Haruko Takeyama, Takato Odagiri, Tsutomu Kageyama, Kiyoko Ogawa-Goto, Pretty Multihartina, Vivi Setiawaty, Krisna Pangesti, Hideki Hasegawa

  PLOS Pathogens 15 1 2019年01月03日
• Shape-dependent adjuvanticity of nanoparticle-conjugated RNA adjuvants for intranasal inactivated influenza vaccines

  Taiyu Tazaki, Koshiro Tabata, Akira Ainai, Yuki Ohara, Shintaro Kobayashi, Takafumi Ninomiya, Yasuko Orba, Hideyuki Mitomo, Tetsuo Nakano, Hideki Hasegawa, Kuniharu Ijiro, Hirofumi Sawa, Tadaki Suzuki, Kenichi Niikura

  RSC Advances 8 30 16527 - 16536 2018年 

  Conjugation with gold nanorods enhanced the adjuvanticity of RNA adjuvant for intranasal inactivated influenza vaccines, providing efficient protection against infection in mice.

MISC

• ウイルスの細胞内増殖過程を標的とする抗ウイルス中和抗体開発の基盤研究

  板倉友香里, 板倉友香里, 田畑耕史郎, 田畑耕史郎, 大場靖子, 大場靖子, 大場靖子, 澤洋文, 澤洋文, 澤洋文, 佐々木道仁, 佐々木道仁 日本ウイルス学会学術集会プログラム・予稿集(Web) 70th 2023年
• ザンビア共和国の蚊及びワニから分離された2種類の新規ウエストナイルウイルス株の病原性解析

  小林広子, 田畑耕史郎, 有泉拓馬, CHAMBARO Herman, PHONGPHAEW Wallaya, SIMULUNDU Edgar, 佐々木道仁, 澤洋文, 澤洋文, 澤洋文, 大場靖子, 大場靖子, 大場靖子 日本ウイルス学会学術集会プログラム・予稿集(Web) 70th 2023年
• 蚊特異的フラビウイルスにおける温度依存的な感染許容機構

  小林広子, 田畑耕史郎, 佐々木道仁, 佐々木道仁, 澤洋文, 澤洋文, 澤洋文, 大場靖子, 大場靖子, 大場靖子 日本分子生物学会年会プログラム・要旨集(Web) 46th 2023年
• プラス鎖RNAウイルスに対して広域的に抗ウイルス活性を示すヌクレオシドアナログの探索

  上村健太朗, 上村健太朗, 上村健太朗, 上村健太朗, 上村健太朗, 登治謙, 佐藤彰彦, 佐藤彰彦, 佐藤彰彦, 鳥羽晋輔, 鳥羽晋輔, 日下部伸治, 日下部伸治, 佐々木道仁, 田畑耕史郎, 大場靖子, 澤洋文, 澤洋文, 松浦善治, 松浦善治, 松田彰, 前仲勝実, 前仲勝実, 前仲勝実 日本薬学会年会要旨集(Web) 143rd 2023年
• SARS-CoV-2感染ハムスターを用いた経口抗ウイルス薬と抗炎症薬の併用治療効果の解析

  佐々木道仁, 杉達紀, 飯田俊, 平田雄一郎, 日下部伸治, 日下部伸治, 小西慧, 小西慧, 板倉友香里, 板倉友香里, 田畑耕史郎, 田畑耕史郎, 岸本麻衣, 岸本麻衣, 小林広子, 有泉拓馬, KITTIYA Intaruck, 登治謙, 鳥羽晋輔, 鳥羽晋輔, 佐藤彰彦, 佐藤彰彦, 佐藤彰彦, 松野啓太, 松野啓太, 山岸潤也, 山岸潤也, 鈴木忠樹, 大場靖子, 大場靖子, 澤洋文, 澤洋文, 澤洋文 日本ウイルス学会学術集会プログラム・予稿集(Web) 70th 2023年

共同研究・競争的資金等の研究課題

• IgA抗体を用いた経鼻噴霧型ワクチンの新規DDS基盤技術の開発

  日本学術振興会：科学研究費助成事業

  研究期間 : 2023年08月 -2025年03月 

  代表者 : 田畑 耕史郎
• 抗フラビウイルス抗体の結合プロファイルを用いたフラビウイルスの血清診断法の確立

  日本学術振興会：科学研究費助成事業

  研究期間 : 2020年04月 -2023年03月 

  代表者 : 田畑 耕史郎

   

  本研究課題「抗フラビウイルス抗体の結合プロファイルを用いたフラビウイルスの血清診断法の確立」では、交叉反応性を含めた抗フラビウイルス抗体の結合活性を網羅的に評価することにより、ウイルス感染によって誘導される特徴的な抗体の結合プロファイルを見出し、これまでに感染歴のあるフラビウイルス種を特定することが可能な新規血清診断法の確立を目的としている。当該年度は、抗フラビウイルス抗体の結合プロファイル取得のためのウイルス抗原パネルの作製、及び作出した抗原パネルに対する標準感染血清の結合プロファイルを取得することを計画した。 フラビウイルスタンパク質において、ウイルス種特異性が高いエピトープとして知られている二量体エンベロープタンパク質（Edimer）をウイルス抗原として使用するため、組換えタンパク質としての作出を試みてきた。これまでの検討により、Edimerは不安的なタンパク質であることから、作製および精製の過程で大部分が凝集してしまうことが明らかになった。 フラビウイルスが感染した細胞から出芽までの過程で、pH依存的に粒子構造を変化させ、宿主のプロテアーゼであるフーリンによってエンベロープ前駆体タンパク質とエンベロープタンパク質（E）が消化されることにより、ウイルス粒子の成熟が進む。消化されたEはウイルス粒子上で、Edimerとして存在することが知られている。しかしながら、感染細胞から出芽するフラビウイルス粒子は部分的に成熟が進んだ未成熟粒子であることが示されている。そこで、精製したウイルス粒子をin vitroのフーリン消化実験を実施することにより、完全に成熟が進んだウイルス粒子を作出し、これを抗体検出抗原として用いることとした。 当該年度以降は、完全成熟フラビウイルス粒子作出のための条件検討、また、標準感染血清を用いて完全成熟ウイルス粒子の抗体検出抗原としての有用性の評価を実施する。