tetano
Editor, Senior Moderator
Nat Immunol
. 2021 May 11.
doi: 10.1038/s41590-021-00942-0. Online ahead of print.
RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells
Taisho Yamada[SUP] 1 2 [/SUP], Seiichi Sato[SUP] 1 2 [/SUP], Yuki Sotoyama[SUP] 1 2 [/SUP], Yasuko Orba[SUP] 3 4 [/SUP], Hirofumi Sawa[SUP] 3 4 5 [/SUP], Hajime Yamauchi[SUP] 1 [/SUP], Michihito Sasaki[SUP] 3 [/SUP], Akinori Takaoka[SUP] 6 7 [/SUP]
Affiliations
Abstract
Efficient immune responses against viral infection are determined by sufficient activation of nucleic acid sensor-mediated innate immunity[SUP]1,2[/SUP]. Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains an ongoing global pandemic. It is an urgent challenge to clarify the innate recognition mechanism to control this virus. Here we show that retinoic acid-inducible gene-I (RIG-I) sufficiently restrains SARS-CoV-2 replication in human lung cells in a type I/III interferon (IFN)-independent manner. RIG-I recognizes the 3' untranslated region of the SARS-CoV-2 RNA genome via the helicase domains, but not the C-terminal domain. This new mode of RIG-I recognition does not stimulate its ATPase, thereby aborting the activation of the conventional mitochondrial antiviral-signaling protein-dependent pathways, which is in accordance with lack of cytokine induction. Nevertheless, the interaction of RIG-I with the viral genome directly abrogates viral RNA-dependent RNA polymerase mediation of the first step of replication. Consistently, genetic ablation of RIG-I allows lung cells to produce viral particles that expressed the viral spike protein. By contrast, the anti-SARS-CoV-2 activity was restored by all-trans retinoic acid treatment through upregulation of RIG-I protein expression in primary lung cells derived from patients with chronic obstructive pulmonary disease. Thus, our findings demonstrate the distinctive role of RIG-I as a restraining factor in the early phase of SARS-CoV-2 infection in human lung cells.
. 2021 May 11.
doi: 10.1038/s41590-021-00942-0. Online ahead of print.
RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells
Taisho Yamada[SUP] 1 2 [/SUP], Seiichi Sato[SUP] 1 2 [/SUP], Yuki Sotoyama[SUP] 1 2 [/SUP], Yasuko Orba[SUP] 3 4 [/SUP], Hirofumi Sawa[SUP] 3 4 5 [/SUP], Hajime Yamauchi[SUP] 1 [/SUP], Michihito Sasaki[SUP] 3 [/SUP], Akinori Takaoka[SUP] 6 7 [/SUP]
Affiliations
- PMID: 33976430
- DOI: 10.1038/s41590-021-00942-0
Abstract
Efficient immune responses against viral infection are determined by sufficient activation of nucleic acid sensor-mediated innate immunity[SUP]1,2[/SUP]. Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains an ongoing global pandemic. It is an urgent challenge to clarify the innate recognition mechanism to control this virus. Here we show that retinoic acid-inducible gene-I (RIG-I) sufficiently restrains SARS-CoV-2 replication in human lung cells in a type I/III interferon (IFN)-independent manner. RIG-I recognizes the 3' untranslated region of the SARS-CoV-2 RNA genome via the helicase domains, but not the C-terminal domain. This new mode of RIG-I recognition does not stimulate its ATPase, thereby aborting the activation of the conventional mitochondrial antiviral-signaling protein-dependent pathways, which is in accordance with lack of cytokine induction. Nevertheless, the interaction of RIG-I with the viral genome directly abrogates viral RNA-dependent RNA polymerase mediation of the first step of replication. Consistently, genetic ablation of RIG-I allows lung cells to produce viral particles that expressed the viral spike protein. By contrast, the anti-SARS-CoV-2 activity was restored by all-trans retinoic acid treatment through upregulation of RIG-I protein expression in primary lung cells derived from patients with chronic obstructive pulmonary disease. Thus, our findings demonstrate the distinctive role of RIG-I as a restraining factor in the early phase of SARS-CoV-2 infection in human lung cells.