Activation and evasion of type I interferon responses by SARS-CoV-2

Lei, Xiaobo; Dong, Xuan; Ma, Ruiyi; Wang, Wenjing; Xiao, Xia; Tian, Zhongqin; Wang, Conghui; Wang, Ying; Li, Li; Ren, Lili; Guo, Fei; Zhao, Zhendong; Zhou, Zhuo; Zou, Xiang; Wang, Jianwei

doi:10.1038/s41467-020-17665-9

Cited by 914 publications

(1,191 citation statements)

References 44 publications

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“…The interferon-stimulated genes IFIT1 and IFITM1 were also upregulated at the latest time points. These results indicate that SARS-CoV-2 induces innate immune activation and interferon response also in hPSC-CMs 29 .…”

Section: Main Textmentioning

confidence: 56%

SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function

Marchianò

Hsiang

Higashi

et al. 2020

Preprint

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Global health has been threatened by the COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2)1. Although considered primarily a respiratory infection, many COVID-19 patients also suffer severe cardiovascular disease2–4. Improving patient care critically relies on understanding if cardiovascular pathology is caused directly by viral infection of cardiac cells or indirectly via systemic inflammation and/or coagulation abnormalities3,5–9. Here we examine the cardiac tropism of SARS-CoV-2 using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) and three-dimensional engineered heart tissues (3D-EHTs). We observe that hPSC-CMs express the viral receptor ACE2 and other viral processing factors, and that SARS-CoV-2 readily infects and replicates within hPSC-CMs, resulting in rapid cell death. Moreover, infected hPSC-CMs show a progressive impairment in both electrophysiological and contractile properties. Thus, COVID-19-related cardiac symptoms likely result from a direct cardiotoxic effect of SARS-CoV-2. Long-term cardiac complications might be possible sequelae in patients who recover from this illness.

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Section: Main Textmentioning

confidence: 56%

SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function

Marchianò

Hsiang

Higashi

et al. 2020

Preprint

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“…Similarly, SARS-CoV-2 ORF6 and MERS-CoV ORF4b are capable of perturbing multiple innate antiviral signaling pathways by target various components of these pathways. 38,44,45 Although cGAS-STING is cytosolic dsDNA sensing pathway, coronaviruses, a family of RNA viruses, also encode viral proteins such as papain-like protease to impair STING function; thus, this pathway is essential in defending against coronavirus infection. 20,21 And the inhibition of cGAS-STING pathway by SARS-CoV-2 ORF9b may suggest that this pathway may play a role in SARS-CoV-2 clearance, thus, drugs or chemicals such as 2’-3’cGAMP that activates this pathway may be considered to be used in COVID-19 treatment.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 ORF9b Antagonizes Type I and III Interferons by Targeting Multiple Components of RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS-STING Signaling Pathways

Han

Zhuang

Zheng

et al. 2020

Preprint

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Severe acute respiratory syndrome corona-virus 2 (SARS-CoV-2), the etiologic agent of the coronavirus disease 2019 (COVID-19), has a catastrophic effect on human health and society. Clinical findings indicated that the suppression of innate antiviral immunity, especially the type I and III interferon (IFN) production, contributes to the pathogenesis of COVID-19. However, how SARS-CoV-2 evades antiviral immunity still needs further investigations. Here, we reported that the open reading frame 9b (ORF9b) protein encoded by the SARS-CoV-2 genome inhibits the activation of type I and III IFN response by targeting multiple molecules of innate antiviral signaling pathways. SARS-CoV-2 ORF9b impaired the induction of type I and III IFNs by Sendai virus or the dsRNA mimic poly (I:C). SARS-CoV-2 ORF9b inhibits the activation of type I and III IFNs induced by the components of cytosolic dsRNA-sensing pathways of RIG-I/MDA5-MAVS signaling, including RIG-I, MDA-5, MAVS, TBK1, and IKKε rather than IRF3-5D, the active form of IRF3. SARS-CoV-2 ORF9b also suppressed the induction of type I and III IFNs by TRIF and STING, the adaptor protein of endosome RNA-sensing pathway of TLR3-TRIF signaling and the adaptor protein of cytosolic DNA-sensing pathway of cGAS-STING signaling, respectively. Mechanistically, SARS-CoV-2 ORF9b protein interacts with RIG-I, MDA-5, MAVS, TRIF, STING, TBK1, and prevents TBK1 phosphorylation, thus impeding the phosphorylation and nuclear trans-localization of IRF3 activation. Overexpression of SARS-CoV-2 ORF9b facilitates the replication of the vesicular stomatitis virus. Therefore, SARS-CoV-2 ORF9b negatively regulates antiviral immunity, thus, facilitate virus replication. This study contributes to our understanding of the molecular mechanism of how SARS-CoV-2 impaired antiviral immunity and providing an essential clue to the pathogenesis of COVID-19.

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“…TLR-3, -7, -8), RIG-I-like receptors (RLRs), and NOD-like receptors (NLRs) (87). To identify the molecular mechanisms that block IFNb production through activation of IRF3/7, several research groups transfected cells individually with all the CoV-2 viral genes and with either RIG I, MDA5, or MAVS (88,89). Among the 27 CoV-2 proteins transfected to cells, they identified nsp14 and orf6 as competent suppressors of IFNb.…”

Section: Interferons and Covid-19mentioning

confidence: 99%

The Role of Type I Interferons in the Pathogenesis and Treatment of COVID-19

2020

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Type I interferons (IFN-I) were first discovered over 60 years ago in a classical experiment by Isaacs and Lindenman, who showed that IFN-Is possess antiviral activity. Later, it became one of the first approved protein drugs using heterologous protein expression systems, which allowed its large-scale production. It has been approved, and widely used in a pleiotropy of diseases, including multiple-sclerosis, hepatitis B and C, and some forms of cancer. Preliminary clinical data has supported its effectiveness against potential pandemic pathogens such as Ebola and SARS. Still, more efficient and specific drugs have taken its place in treating such diseases. The COVID-19 global pandemic has again lifted the status of IFN-Is to become one of the more promising drug candidates, with initial clinical trials showing promising results in reducing the severity and duration of the disease. Although SARS-CoV-2 inhibits the production of IFNb and thus obstructs the innate immune response to this virus, it is sensitive to the antiviral activity of externally administrated IFN-Is. In this review I discuss the diverse modes of biological actions of IFN-Is and how these are related to biophysical parameters of IFN-I-receptor interaction and cell-type specificity in light of the large variety of binding affinities of the different IFN-I subtypes towards the common interferon receptor. Furthermore, I discuss how these may guide the optimized use IFN-Is in combatting COVID-19.

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Activation and evasion of type I interferon responses by SARS-CoV-2

Cited by 914 publications

References 44 publications

SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function

SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical function

SARS-CoV-2 ORF9b Antagonizes Type I and III Interferons by Targeting Multiple Components of RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS-STING Signaling Pathways

The Role of Type I Interferons in the Pathogenesis and Treatment of COVID-19

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