Publikationsdatenbank

The NSP4 T492I mutation increases SARS-CoV-2 infectivity by altering non-structural protein cleavage (2023)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Lin, Xiaoyuan (WE 5)

Sha, Zhou

Trimpert, Jakob (WE 5)

Kunec, Dusan (WE 5)

Jiang, Chen

Xiong, Yan

Xu, Binbin

Zhu, Zhenglin

Xue, Weiwei

Wu, Haibo

Quelle

Cell host & microbe

Bandzählung: 31

Heftzählung: 7

Seiten: 1170 – 1184.e7

ISSN: 1934-6069

Sprache

Englisch

Verweise

URL (Volltext): https://pubmed.ncbi.nlm.nih.gov/37402373/

DOI: 10.1016/j.chom.2023.06.002

Pubmed: 37402373

Kontakt

Institut für Virologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51833
virologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

The historically dominant SARS-CoV-2 Delta variant and the currently dominant Omicron variants carry a T492I substitution within the non-structural protein 4 (NSP4). Based on in silico analyses, we hypothesized that the T492I mutation increases viral transmissibility and adaptability, which we confirmed with competition experiments in hamster and human airway tissue culture models. Furthermore, we showed that the T492I mutation increases the replication capacity and infectiveness of the virus and improves its ability to evade host immune responses. Mechanistically, the T492I mutation increases the cleavage efficiency of the viral main protease NSP5 by enhancing enzyme-substrate binding, which increases production of nearly all non-structural proteins processed by NSP5. Importantly, the T492I mutation suppresses viral-RNA-associated chemokine production in monocytic macrophages, which may contribute to the attenuated pathogenicity of Omicron variants. Our results highlight the importance of NSP4 adaptation in the evolutionary dynamics of SARS-CoV-2.