MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Recent studies have profiled the innate immune signatures in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and suggest that cellular responses to viral challenge may affect disease severity. Yet the molecular events that underlie cellular recognition and response to SARS-CoV-2 infection remain to be elucidated. Here, we find that SARS-CoV-2 replication induces a delayed interferon (IFN) response in lung epithelial cells. By screening 16 putative sensors involved in sensing of RNA virus infection, we found that MDA5 and LGP2 primarily regulate IFN induction in response to SARS-CoV-2 infection. Further analyses revealed that viral intermediates specifically activate the IFN response through MDA5-mediated sensing. Additionally, we find that IRF3, IRF5, and NF-κB/p65 are the key transcription factors regulating the IFN response during SARS-CoV-2 infection. In summary, these findings provide critical insights into the molecular basis of the innate immune recognition and signaling response to SARS-CoV-2.

Graphical Abstract

Highlights

•

SARS-CoV-2 replication induces a delayed IFN response in lung epithelial cells
•

MDA5 and LGP2 are the major sensors recognizing SARS-CoV-2 infection
•

Viral intermediates activate the IFN response through MDA5-mediated sensing
•

IRF3, IRF5, and NF-κB/p65 are required for the IFN response induced by SARS-CoV-2

Abstract

The molecular events that underlie innate immune recognition and response to SARS-CoV-2 infection remain unclear. Yin et al. report that SARS-CoV-2 replication induces a delayed interferon (IFN) response that is triggered by sensing of viral RNA through the MDA5 pattern recognition receptor.

Related collections

Most cited references 66

Record: found
Abstract: found
Article: found

Is Open Access

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)

Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.

0 comments Cited 10275 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

0 comments Cited 9873 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

A new coronavirus associated with human respiratory disease in China

Fan Wu, Su Zhao, Bin Yu … (2020)

Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health 1–3 . Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing 4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here ‘WH-Human 1’ coronavirus (and has also been referred to as ‘2019-nCoV’). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China 5 . This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.

0 comments Cited 5402 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Cell Rep

Journal ID (iso-abbrev): Cell Rep

Title: Cell Reports

Publisher: The Authors.

ISSN (Electronic): 2211-1247

Publication date PMC-release: 12 January 2021

Publication date (Print): 12 January 2021

Publication date (Electronic): 12 January 2021

Volume: 34

Issue: 2

Page: 108628

Affiliations

[1 ]Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA

[2 ]State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, P.R. China

[3 ]Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan

[4 ]Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo 162-8640, Japan

[5 ]Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

[6 ]Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

[7 ]Functional Genomics Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA

[8 ]Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, IL 60201, USA

[9 ]Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

[10 ]The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

Author notes

[∗ ]Corresponding author

[11]

Lead Contact

Article

Publisher Item ID: S2211-1247(20)31617-X Publisher ID: 108628

DOI: 10.1016/j.celrep.2020.108628

PMC ID: 7832566

PubMed ID: 33440148

SO-VID: 273121f2-7a71-475d-91bc-7a0815152c86

License:

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

History

Date received : 23 August 2020

Date revision received : 12 November 2020

Date accepted : 18 December 2020

Comments

Comment on this article

scite_

Cited by 189

See all cited by

Most referenced authors 3,965

See all reference authors

- Version 1

MDA5 Governs the Innate Immune Response to SARS-CoV-2 in Lung Epithelial Cells

Read this article at

Abstract

Graphical Abstract

Highlights

Abstract

Related collections

Novel Coronavirus Disease COVID-19

Most cited references 66

A pneumonia outbreak associated with a new coronavirus of probable bat origin

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

A new coronavirus associated with human respiratory disease in China

Author and article information

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 705

Cited by 189

Most referenced authors 3,965