SARS-CoV-2 nsp15 enhances viral virulence by subverting host antiviral defenses
Abstract
SARS-CoV-2 encodes numerous virulence factors, yet their precise mechanisms of action remain unknown. We provide evidence that the SARS-CoV-2 nonstructural protein 15 (nsp15) enhances viral virulence by suppressing the production of viral double-stranded (dsRNA), a potent inducer of antiviral signaling. The viral variants lacking nsp15 endoribonuclease activity elicited higher innate immune responses and exhibited reduced replication in human stem cell–derived lung alveolar type II epithelial cells, as well as in the lungs of infected hamsters. Consistently, these variants caused significantly less weight loss and mortality compared to wild-type (WT) virus in K18-hACE2 mice. Mechanistically, the cells infected with nsp15 mutants accumulated more viral dsRNA, causing enhanced stimulation of the interferon pathway. Chemical inhibition of interferon signaling dampened immune responses to nsp15 mutants and restored their replication to levels similar to the WT virus. These findings indicate that the endoribonuclease activity of nsp15 contributes to viral virulence by limiting the accumulation of viral dsRNA, thereby allowing robust replication with reduced activation of the host innate immune response.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (24)
Allen Caobi
Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine
Chia-Ming Su
Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine
Christian M. Beusch
Devin Kenney
Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine
Tamarand L. Darling
Department of Medicine, Washington University School of Medicine
Shuchen Feng
Department of Microbiology and Immunology, Loyola University Chicago Stritch School of Medicine
Marc Semaan
Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine
Alan Wacquiez
Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine
Nathan L. Sanders
The Pulmonary Center, Boston University Chobanian and Avedisian School of Medicine
Ena S. Tully
Department of Biochemistry, Institute for Molecular Virology, Center for Quantitative Cell Imaging, University of Wisconsin-Madison
Da-Yuan Chen
Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine
Monika Evdokimova
Department of Microbiology and Immunology, Loyola University Chicago Stritch School of Medicine
Zhen Ding
Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine
Dakota Jones
Konstantinos-Dionysios Alysandratos
Joseph P. Mizgerd
National Emerging Infectious Diseases Laboratories, Boston University
Robert N. Kirchdoerfer
Darrell N. Kotton
Florian Douam
National Emerging Infectious Diseases Laboratories, Boston University
Nicholas A. Crossland
National Emerging Infectious Diseases Laboratories, Boston University
Adrianus C. M. Boon
Department of Medicine, Washington University School of Medicine
David E. Gordon
Susan C. Baker
Department of Microbiology and Immunology, Loyola University Chicago Stritch School of Medicine
Mohsan Saeed
Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine