抄録
Many SARS-CoV-2 variants with naturally acquired mutations have emerged. These mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has been investigated, sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains largely unexplored. Here, we demonstrate that two recently emerging mutations in the receptor-binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429 and B.1.617) and Y453F (in B.1.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce affinity toward the host entry receptor ACE2. Notably, the L452R mutation increases spike stability, viral infectivity, viral fusogenicity, and thereby promotes viral replication. These data suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes and that a further threat of the SARS-CoV-2 pandemic is escape from cellular immunity.
| 本文言語 | 英語 |
|---|---|
| ページ（範囲） | 1124-1136.e11 |
| ジャーナル | Cell Host and Microbe |
| 巻 | 29 |
| 号 | 7 |
| DOI | |
| 出版ステータス | 出版済み - 7月 14 2021 |
!!!All Science Journal Classification (ASJC) codes
- 寄生虫科
- 微生物学
- ウイルス学
フィンガープリント
「SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。引用スタイル
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SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity. / The Genotype to Phenotype Japan (G2P-Japan) Consortium.
In: Cell Host and Microbe, Vol. 29, No. 7, 14.07.2021, p. 1124-1136.e11.研究成果: ジャーナルへの寄稿 › 学術誌 › 査読
}
TY - JOUR
T1 - SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity
AU - The Genotype to Phenotype Japan (G2P-Japan) Consortium
AU - Motozono, Chihiro
AU - Toyoda, Mako
AU - Zahradnik, Jiri
AU - Saito, Akatsuki
AU - Nasser, Hesham
AU - Tan, Toong Seng
AU - Ngare, Isaac
AU - Kimura, Izumi
AU - Uriu, Keiya
AU - Kosugi, Yusuke
AU - Yue, Yuan
AU - Shimizu, Ryo
AU - Ito, Jumpei
AU - Torii, Shiho
AU - Yonekawa, Akiko
AU - Shimono, Nobuyuki
AU - Nagasaki, Yoji
AU - Minami, Rumi
AU - Toya, Takashi
AU - Sekiya, Noritaka
AU - Fukuhara, Takasuke
AU - Matsuura, Yoshiharu
AU - Schreiber, Gideon
AU - Ikeda, Terumasa
AU - Nakagawa, So
AU - Ueno, Takamasa
AU - Sato, Kei
N1 - Funding Information: This study was supported in part by AMED Research Program on Emerging and Re-emerging Infectious Diseases 20fk0108163 (to A.S.), 20fk0108539 (to T.U.), 20fk0108146 (to K.S.), 19fk0108171 (to S.N. and K.S.), 20fk0108270 (to K.S.), and 20fk0108413 (to T.I., S.N., and K.S.); AMED Research Program on HIV/AIDS 21fk0410046 (to C.M.), 20fk0410019 (to T.U. and K.S.), 20fk0410014 (to K.S.), and 21fk0410039 (to K.S.); AMED Japan Program for Infectious Diseases Research and Infrastructure 20wm0325009 (to A.S.); JST A-STEP JPMJTM20SL (to T.I.); JST J-RAPID JPMJJR2007 (to K.S.); JST SICORP (e-ASIA) JPMJSC20U1 (to K.S.); JST SICORP JPMJSC21U5 (to K.S.); JST CREST JPMJCR20H6 (to S.N,) and JPMJCR20H4 (to K.S); JSPS KAKENHI Grant-in-Aid for Scientific Research B 18H02662 (to K.S.) and 21H02737 (to K.S.); JSPS KAKENHI Grant-in-Aid for Scientific Research on Innovative Areas 16H06429 (to S.N. and K.S.), 16K21723 (to S.N. and K.S.), 17H05823 (to S.N.), 17H05813 (to K.S.), 19H04843 (to S.N.), and 19H04826 (to K.S.); JSPS Fund for the Promotion of Joint International Research (Fostering Joint International Research) 18KK0447 (to K.S.); JSPS Core-to-Core Program JPJSCCB20190009 (to T.U.) and JPJSCCA20190008 (A. Advanced Research Networks) (to K.S.); JSPS Research Fellow DC1 19J20488 (to I.K.); JSPS Leading Initiative for Excellent Young Researchers (LEADER) (to T.I.); ONO Medical Research Foundation (to K.S.); Ichiro Kanehara Foundation (to K.S.); Lotte Foundation (to K.S.); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to K.S.); Daiichi Sankyo Foundation of Life Science (to K.S.); Sumitomo Foundation (to K.S.); Uehara Foundation (to K.S.); Takeda Science Foundation (to C.M., T.I., and K.S.); The Tokyo Biochemical Research Foundation (to K.S.); Mitsubishi Foundation (to T.I.); Shin-Nihon Foundation of Advanced Medical Research (to T.I.); an intramural grant from Kumamoto University COVID-19 Research Projects (AMABIE) (to C.M., T.I., and T.U.); Kumamoto University International Collaborative Research Grants (to T.U.); Intercontinental Research and Educational Platform Aiming for Eradication of HIV/AIDS (to T.I. and T.U.); 2020 Tokai University School of Medicine Research Aid (to S.N.); and Joint Usage/Research Center program of Institute for Frontier Life and Medical Sciences, Kyoto University (to K.S.). T.S.T and I.N. are the recipients of the doctoral course scholarship from Japanese Government. Funding Information: We would like to thank all members belonging to the Genotype to Phenotype Japan (G2P-Japan) Consortium. We thank Drs. Sho Fujiwara, Kazuaki Fukushima, Masaru Tanaka, and Akifumi Imamura (Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Japan) for supporting the collection of COVID-19 convalescent samples; Dr. Mizuki Kitamatsu and Mr. Yoshiki Aritsu (Kindai University, Japan) for supporting the preparation of synthetic peptides; Drs. Hiroyuki Kishi and Hiroshi Hamana (University of Toyama, Japan) for helpful suggestions; and Dr. Kenzo Tokunaga (National Institute of Infectious Diseases, Japan), Dr. Shuetsu Fukushi (National Institute of Infectious Diseases, Japan), Dr. Masafumi Takiguchi (Kumamoto University, Japan), and Dr. Jin Gohda (The University of Tokyo, Japan) for providing plasmids, reagents, and cells. The super-computing resource was provided by Human Genome Center at The University of Tokyo and the NIG supercomputer at ROIS National Institute of Genetics. This study was supported in part by AMED Research Program on Emerging and Re-emerging Infectious Diseases 20fk0108163 (to A.S.), 20fk0108539 (to T.U.), 20fk0108146 (to K.S.), 19fk0108171 (to S.N. and K.S.), 20fk0108270 (to K.S.), and 20fk0108413 (to T.I. S.N. and K.S.); AMED Research Program on HIV/AIDS 21fk0410046 (to C.M.), 20fk0410019 (to T.U. and K.S.), 20fk0410014 (to K.S.), and 21fk0410039 (to K.S.); AMED Japan Program for Infectious Diseases Research and Infrastructure 20wm0325009 (to A.S.); JST A-STEP JPMJTM20SL (to T.I.); JST J-RAPID JPMJJR2007 (to K.S.); JST SICORP (e-ASIA) JPMJSC20U1 (to K.S.); JST SICORP JPMJSC21U5 (to K.S.); JST CREST JPMJCR20H6 (to S.N,) and JPMJCR20H4 (to K.S); JSPS KAKENHI Grant-in-Aid for Scientific Research B 18H02662 (to K.S.) and 21H02737 (to K.S.); JSPS KAKENHI Grant-in-Aid for Scientific Research on Innovative Areas 16H06429 (to S.N. and K.S.), 16K21723 (to S.N. and K.S.), 17H05823 (to S.N.), 17H05813 (to K.S.), 19H04843 (to S.N.), and 19H04826 (to K.S.); JSPS Fund for the Promotion of Joint International Research (Fostering Joint International Research) 18KK0447 (to K.S.); JSPS Core-to-Core Program JPJSCCB20190009 (to T.U.) and JPJSCCA20190008 (A. Advanced Research Networks) (to K.S.); JSPS Research Fellow DC1 19J20488 (to I.K.); JSPS Leading Initiative for Excellent Young Researchers (LEADER) (to T.I.); ONO Medical Research Foundation (to K.S.); Ichiro Kanehara Foundation (to K.S.); Lotte Foundation (to K.S.); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to K.S.); Daiichi Sankyo Foundation of Life Science (to K.S.); Sumitomo Foundation (to K.S.); Uehara Foundation (to K.S.); Takeda Science Foundation (to C.M. T.I. and K.S.); The Tokyo Biochemical Research Foundation (to K.S.); Mitsubishi Foundation (to T.I.); Shin-Nihon Foundation of Advanced Medical Research (to T.I.); an intramural grant from Kumamoto University COVID-19 Research Projects (AMABIE) (to C.M. T.I. and T.U.); Kumamoto University International Collaborative Research Grants (to T.U.); Intercontinental Research and Educational Platform Aiming for Eradication of HIV/AIDS (to T.I. and T.U.); 2020 Tokai University School of Medicine Research Aid (to S.N.); and Joint Usage/Research Center program of Institute for Frontier Life and Medical Sciences, Kyoto University (to K.S.). T.S.T and I.N. are the recipients of the doctoral course scholarship from Japanese Government. C.M. M.T. J.Z. A.S. H.N. T.S.T. I.N. I.K. K.U. Y.Y. R.S. T.I. and K.S. performed the experiments. S.T. T.F. G.S. and Y.M. prepared experimental materials. J.Z. and Y.K. performed structural analysis. S.N. performed molecular phylogenetic analysis. A.Y. N. Shimoto, Y.N. R.M. T.T. and N. Sekiya performed clinical analysis and collected clinical samples. C.M. M.T. J.Z. A.S. J.I. T.I. S.N. T.U. and K.S. designed the experiments and interpreted the results. K.S. wrote the original manuscript. C.M. J.Z. A.S. T.I. S.N, and T.U. modified the manuscript. All authors reviewed and proofread the manuscript. The Genotype to Phenotype Japan (G2P-Japan) Consortium contributed to the project administration. The authors declare no competing interests. Publisher Copyright: © 2021 The Authors
PY - 2021/7/14
Y1 - 2021/7/14
N2 - Many SARS-CoV-2 variants with naturally acquired mutations have emerged. These mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has been investigated, sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains largely unexplored. Here, we demonstrate that two recently emerging mutations in the receptor-binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429 and B.1.617) and Y453F (in B.1.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce affinity toward the host entry receptor ACE2. Notably, the L452R mutation increases spike stability, viral infectivity, viral fusogenicity, and thereby promotes viral replication. These data suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes and that a further threat of the SARS-CoV-2 pandemic is escape from cellular immunity.
AB - Many SARS-CoV-2 variants with naturally acquired mutations have emerged. These mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has been investigated, sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains largely unexplored. Here, we demonstrate that two recently emerging mutations in the receptor-binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429 and B.1.617) and Y453F (in B.1.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce affinity toward the host entry receptor ACE2. Notably, the L452R mutation increases spike stability, viral infectivity, viral fusogenicity, and thereby promotes viral replication. These data suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes and that a further threat of the SARS-CoV-2 pandemic is escape from cellular immunity.
UR - http://www.scopus.com/inward/record.url?scp=85108960663&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85108960663&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2021.06.006
DO - 10.1016/j.chom.2021.06.006
M3 - Article
C2 - 34171266
AN - SCOPUS:85108960663
VL - 29
SP - 1124-1136.e11
JO - Cell Host and Microbe
JF - Cell Host and Microbe
SN - 1931-3128
IS - 7
ER -