Journal ArticleDOI
SARS-CoV-2 Nonstructural Protein 1 Inhibits the Interferon Response by Causing Depletion of Key Host Signaling Factors.
Anil Kumar,Ray Ishida,Tania Strilets,Jamie Cole,Joaquin Lopez-Orozco,Nawell Fayad,Alberto Felix-Lopez,Mohamed Elaish,Danyel Evseev,Katharine E. Magor,Lara K. Mahal,Les P. Nagata,David H. Evans,Tom C. Hobman +13 more
TLDR
It is shown that the IFN response is efficiently blocked during SARS-CoV-2 infection, a process that is mediated in large part by nonstructural protein 1 and nucleocapsid.Abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. While previous studies have shown that several SARS-CoV-2 proteins can antagonize the interferon (IFN) response, some of the mechanisms by which they do so are not well understood. In this study, we describe two novel mechanisms by which SARS-CoV-2 blocks the IFN pathway. Type I IFNs and IFN-stimulated genes (ISGs) were poorly induced during SARS-CoV-2 infection, and once infection was established, cells were highly resistant to ectopic induction of IFNs and ISGs. Levels of two key IFN signaling pathway components, Tyk2 and STAT2, were significantly lower in SARS-CoV-2-infected cells. Expression of nonstructural protein 1 (NSP1) or nucleocapsid in the absence of other viral proteins was sufficient to block IFN induction, but only NSP1 was able to inhibit IFN signaling. Mapping studies suggest that NSP1 prevents IFN induction in part by blocking IRF3 phosphorylation. In addition, NSP1-induced depletion of Tyk2 and STAT2 dampened ISG induction. Together, our data provide new insights into how SARS-CoV-2 successfully evades the IFN system to establish infection. IMPORTANCE SARS-CoV-2 is the causative agent of COVID-19, a serious disease that can have a myriad of symptoms from loss of taste and smell to pneumonia and hypercoagulation. The rapid spread of SARS-CoV-2 can be attributed in part to asymptomatic transmission, where infected individuals shed large amounts of virus before the onset of disease. This is likely due to the ability of SARS-CoV-2 to effectively suppress the innate immune system, including the IFN response. Indeed, we show that the IFN response is efficiently blocked during SARS-CoV-2 infection, a process that is mediated in large part by nonstructural protein 1 and nucleocapsid. Our study provides new insights on how SARS-CoV-2 evades the IFN response to successfully establish infection. These findings should be considered for the development and administration of therapeutics against SARS-CoV-2.read more
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SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19
TL;DR: SARS-CoV-2’s ability to induce autoimmune and autoinflammatory pathways of tissue invasion and development of both immunosuppressive and hyperergic mechanisms of systemic inflammation is critical at this stage of infection.
Journal ArticleDOI
Type I interferons and SARS-CoV-2: from cells to organisms
TL;DR: In this article , the interplay between type I interferons and SARS-CoV-2 is discussed, and the early administration of exogenous type I IFNs improves infection control.
Journal ArticleDOI
Type I Interferons in COVID-19 Pathogenesis.
TL;DR: In this article, the authors summarize the virus-mediated evasion of the type I interferon (IFN) responses and the viral functions involved, the genetic basis of IFN production in SARS-CoV-2 infection and the progress of clinical trials designed to utilize type I IFN as a potential therapeutic tool.
Journal ArticleDOI
Coronavirus Nsp1: Immune Response Suppression and Protein Expression Inhibition.
TL;DR: In this paper, the authors discuss current data about suppression of the immune responses and inhibition of protein synthesis induced by coronavirus Nsp1, as well as the prospect of liveattenuated vaccine development with virulence-attenuated viruses with mutations in Nsp 1.
Journal ArticleDOI
Interferon induction, evasion, and paradoxical roles during SARS‐CoV‐2 infection
TL;DR: It is essential to understand the relationships between SARS‐CoV‐2 and IFN to better inform treatments that exploit IFN functions to alleviate COVID‐19.
References
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Journal ArticleDOI
A Novel Coronavirus from Patients with Pneumonia in China, 2019.
Na Zhu,Dingyu Zhang,Wenling Wang,Xingwang Li,Bo Yang,Jingdong Song,Xiang Zhao,Baoying Huang,Weifeng Shi,Roujian Lu,Peihua Niu,Faxian Zhan,Xuejun Ma,Dayan Wang,Wenbo Xu,Wenbo Xu,Guizhen Wu,George F. Gao,Wenjie Tan +18 more
TL;DR: Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily, which is the seventh member of the family of coronaviruses that infect humans.
Journal ArticleDOI
Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China.
Dawei Wang,Bo Hu,Chang Hu,Fangfang Zhu,Xing Liu,Jing Zhang,Binbin Wang,Hui Xiang,Zhenshun Cheng,Yong Xiong,Yan Zhao,Yirong Li,Xinghuan Wang,Zhiyong Peng +13 more
TL;DR: The epidemiological and clinical characteristics of novel coronavirus (2019-nCoV)-infected pneumonia in Wuhan, China, and hospital-associated transmission as the presumed mechanism of infection for affected health professionals and hospitalized patients are described.
Journal ArticleDOI
Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.
Wenhui Li,Michael Moore,Natalya Vasilieva,Jianhua Sui,Swee Kee Wong,Michael A. Berne,Mohan Somasundaran,John L. Sullivan,Katherine Luzuriaga,Thomas C. Greenough,Hyeryun Choe,Michael Farzan +11 more
TL;DR: It is found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells, indicating that ACE2 is a functional receptor for SARS-CoV.
Journal ArticleDOI
The proximal origin of SARS-CoV-2.
Kristian G. Andersen,Kristian G. Andersen,Andrew Rambaut,W. Ian Lipkin,Edward C. Holmes,Robert F. Garry +5 more
TL;DR: It is shown that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus, and scenarios by which they could have arisen are discussed.
Journal ArticleDOI
Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility.
Melissa M. Arons,Kelly M Hatfield,Sujan C Reddy,Anne Kimball,Allison E James,Jesica R. Jacobs,Joanne Taylor,Kevin B. Spicer,Ana C Bardossy,Lisa P. Oakley,Sukarma Tanwar,Jonathan W Dyal,Josh Harney,Zeshan Chisty,Jeneita M. Bell,Mark Methner,Prabasaj Paul,Christina M. Carlson,Heather P. McLaughlin,Natalie J. Thornburg,Suxiang Tong,Azaibi Tamin,Ying Tao,Anna Uehara,Jennifer L Harcourt,Shauna Clark,Claire Brostrom-Smith,Libby C. Page,Meagan Kay,James S. Lewis,Patty Montgomery,Nimalie D. Stone,Thomas A. Clark,Margaret A. Honein,Jeffrey S. Duchin,John A. Jernigan +35 more
TL;DR: Rapid and widespread transmission of SARS-CoV-2 was demonstrated in this skilled nursing facility and infection-control strategies focused solely on symptomatic residents were not sufficient to prevent transmission.