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農学部 獣医学科 |
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准教授 |
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Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity. 査読あり 国際共著
Meng B, Abdullahi A, Ferreira IATM, Goonawardane N, Saito A, Kimura I, Yamasoba D, Gerber PP, Fatihi S, Rathore S, Zepeda SK, Papa G, Kemp SA, Ikeda T, Toyoda M, Tan TS, Kuramochi J, Mitsunaga S, Ueno T, Shirakawa K, Takaori-Kondo A, Brevini T, Mallery DL, Charles OJ, CITIID-NIHR BioResource COVID- Collaboration., Genotype to Phenotype Japan (GP-Japan) Consortium members., Ecuador-COVID19 Consortium., Bowen JE, Joshi A, Walls AC, Jackson L, Martin D, Smith KGC, Bradley J, Briggs JAG, Choi J, Madissoon E, Meyer K, Mlcochova P, Ceron-Gutierrez L, Doffinger R, Teichmann SA, Fisher AJ, Pizzuto MS, de Marco A, Corti D, Hosmillo M, Lee JH, James LC, Thukral L, Veesler D, Sigal A, Sampaziotis F, Goodfellow IG, Matheson NJ, Sato K, Gupta RK
Nature 603 ( 7902 ) 706 - 714 2022年2月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Springer Science and Business Media LLC
Abstract
The SARS-CoV-2 Omicron BA.1 variant emerged in 2021<sup>1</sup> and has multiple mutations in its spike protein<sup>2</sup>. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways<sup>3</sup> demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis. -
Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation. 査読あり
Saito A, Irie T, Suzuki R, Maemura T, Nasser H, Uriu K, Kosugi Y, Shirakawa K, Sadamasu K, Kimura I, Ito J, Wu J, Iwatsuki-Horimoto K, Ito M, Yamayoshi S, Loeber S, Tsuda M, Wang L, Ozono S, Butlertanaka EP, Tanaka YL, Shimizu R, Shimizu K, Yoshimatsu K, Kawabata R, Sakaguchi T, Tokunaga K, Yoshida I, Asakura H, Nagashima M, Kazuma Y, Nomura R, Horisawa Y, Yoshimura K, Takaori-Kondo A, Imai M, Genotype to Phenotype Japan (G2P-Japan) Consortium., Tanaka S, Nakagawa S, Ikeda T, Fukuhara T, Kawaoka Y, Sato K
Nature 602 ( 7896 ) 300 - 306 2021年11月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Springer Science and Business Media LLC
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Cell response analysis in SARS-CoV-2 infected bronchial organoids. 査読あり 国際誌
Sano E, Suzuki T, Hashimoto R, Itoh Y, Sakamoto A, Sakai Y, Saito A, Okuzaki D, Motooka D, Muramoto Y, Noda T, Takasaki T, Sakuragi JI, Minami S, Kobayashi T, Yamamoto T, Matsumura Y, Nagao M, Okamoto T, Takayama K
Communications biology 5 ( 1 ) 516 - 516 2022年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Springer Science and Business Media LLC
Abstract
The development of an in vitro cell model that can be used to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research is expected. Here we conducted infection experiments in bronchial organoids (BO) and an BO-derived air-liquid interface model (BO-ALI) using 8 SARS-CoV-2 variants. The infection efficiency in BO-ALI was more than 1,000 times higher than that in BO. Among the bronchial epithelial cells, we found that ciliated cells were infected with the virus, but basal cells were not. Ciliated cells died 7 days after the viral infection, but basal cells survived after the viral infection and differentiated into ciliated cells. Fibroblast growth factor 10 signaling was essential for this differentiation. These results indicate that BO and BO-ALI may be used not only to evaluate the cell response to SARS-CoV-2 and coronavirus disease 2019 (COVID-19) therapeutic agents, but also for airway regeneration studies. -
Maya Shofa, Tomotaka Okamura, Emiko Urano, Yoshiharu Matsuura, Yasuhiro Yasutomi, Akatsuki Saito
International Journal of Molecular Sciences 23 ( 22 ) 14002 - 14002 2022年11月
担当区分：最終著者, 責任著者 掲載種別：研究論文（学術雑誌） 出版者・発行元：MDPI AG
Zika virus (ZIKV) outbreaks in Central and South America caused severe public health problems in 2015 and 2016. These outbreaks were finally contained through several methods, including mosquito control using insecticides and repellents. Additionally, the development of herd immunity in these countries might have contributed to containing the epidemic. While ZIKV is mainly transmitted by mosquito bites and mucosal transmission via bodily fluids, including the semen of infected individuals, has also been reported. We evaluated the effect of mucosal ZIKV infection on continuous subcutaneous challenges in a cynomolgus monkey model. Repeated intravaginal inoculations of ZIKV did not induce detectable viremia or clinical symptoms, and all animals developed a potent neutralizing antibody, protecting animals from the subsequent subcutaneous superchallenge. These results suggest that viral replication at mucosal sites can induce protective immunity without causing systemic viremia or symptoms.
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Generation of a bovine cell line for gene engineering using an HIV-1-based lentiviral vector. 査読あり
Morizako N, Butlertanaka EP, Tanaka YL, Shibata H, Okabayashi T, Mekata H, Saito A
Scientific reports 12 ( 1 ) 16952 2022年10月
担当区分：最終著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Springer Science and Business Media LLC
Abstract
Human immunodeficiency virus type 1 (HIV-1)-based lentiviral vectors are indispensable tools for gene engineering in mammalian cells. Conversely, lentiviral vector transduction is severely inhibited in bovine cells. Previous studies demonstrated that this inhibition is caused by the anti-lentiviral host factor tripartite motif containing 5 (TRIM5), which targets incoming HIV-1 virions by interacting with the viral capsid. In this study, we investigated several methods for overcoming the limited applicability of lentiviral vectors in bovine cells. First, we demonstrated that the SPRY domain of bovine TRIM5 is the major determinant of anti-viral activity. Second, we found that mutations that allow the capsid to evade rhesus macaque TRIM5α minimally rescued HIV-1 infectivity in bovine-derived MDBK cells. Third, we found that cyclosporine A, which relieves the inhibition of HIV-1 infection in monkey cells, significantly rescued the impaired HIV-1 infectivity in MDBK cells. Lastly, we successfully generated a bovine cell line lacking intact TRIM5 using the CRISPR/Cas9 technique. This TRIM5 knockout cell line displayed significantly higher susceptibility to an HIV-1-based lentiviral vector. In conclusion, our findings provide a promising gene engineering strategy for bovine cells, thereby contributing to innovations in agriculture and improvements in animal health.
科研費（文科省・学振・厚労省）獲得実績 【 表示 ／ 非表示 】
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動物フォーミーウイルスベクターの基盤構築と牛伝染性リンパ腫ワクチンの開発
研究課題/領域番号：22H02500 2022年04月 - 2026年03月
科学研究費補助金 基盤研究(B)
担当区分：研究分担者
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ゲノムワイドスクリーニングに基づくSFTS発症小動物モデルの樹立と治療開発展開
研究課題/領域番号：21H02361 2021年04月 - 2026年03月
独立行政法人日本学術振興会 科学研究費補助金 基盤研究(B)
岡林 環樹、斎藤 暁、山田 健太郎
担当区分：研究分担者
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インターフェロン誘導性宿主因子によるフラビウイルス宿主域決定機序の体系的理解
研究課題/領域番号：19K06382 2019年04月 - 2022年03月
科学研究費補助金 基盤研究(C)
担当区分：研究代表者
受託研究受入実績 【 表示 ／ 非表示 】
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迅速なエイズウイルスの分離方法の確立
2022年04月 - 2024年03月
国立研究開発法人医薬基盤･健康･栄養研究所 一般受託研究
担当区分：研究代表者 受託研究区分：一般受託研究
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次亜塩素酸ナトリウム（製品名：SteriNa)によるSARS-CoV-2不活化試験
2020年12月 - 2021年06月
SSP株式会社 一般受託研究
担当区分：研究分担者 受託研究区分：一般受託研究