Evasion of Type I Interferon by SARS-CoV-2

Xia, Hongjie; Cao, Zongjie; Xie, Xuping; Zhang, Xianwen; Chen, John Yun Chung; Wang, Hualei; Menachery, Vineet D.; Rajsbaum, Ricardo; Shi, Pei Yong

doi:10.1016/j.celrep.2020.108234

Cited by 868 publications

(1,231 citation statements)

References 55 publications

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“…The rapidity and burst-size of SARS-CoV-2 replication in culture may render other relevant antiviral proteins difficult to measure. Furthermore, the virus encodes a number of antagonists of antiviral pathways (Xia et al, 2020). As shown clearly by the IFNg phenotype, expression of other ISGs or their differential regulation may make a give antiviral more less potent.…”

Section: Ifitm2mentioning

confidence: 99%

The polybasic cleavage site in the SARS-CoV-2 spike modulates viral sensitivity to Type I IFN and IFITM2

Winstone

Brotos

Reid

et al. 2020

Preprint

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The cellular entry of severe acute respiratory syndrome-associated coronaviruses types 1 and 2 (SARS-CoV-1 and -2) requires sequential protease processing of the viral spike glycoprotein (S). The presence of a polybasic cleavage site in SARS-CoV-2 S at the S1/S2 boundary has been suggested to be a factor in the increased transmissibility of SARS-CoV-2 compared to SARS-CoV-1 by facilitating maturation of the S precursor by furin-like proteases in the producer cells rather than endosomal cathepsins in the target. We investigate the relevance of the polybasic cleavage site in the route of entry of SARS-CoV-2 and the consequences this has for sensitivity to interferons, and more specifically, the IFN-induced transmembrane (IFITM) protein family that inhibit entry of diverse enveloped viruses. We found that SARS-CoV-2 is restricted predominantly by IFITM2 and the degree of this restriction is governed by route of viral entry. Removal of the cleavage site in the spike protein renders SARS-CoV-2 entry highly pH- and cathepsin-dependent in late endosomes where, like SARS-CoV-1 S, it is more sensitive to IFITM2 restriction. Furthermore, we find that potent inhibition of SARS-CoV-2 replication by type I but not type II IFNs is alleviated by targeted depletion of IFITM2 expression. We propose that the polybasic cleavage site allows SARS-CoV-2 to mediate viral entry in a pH-independent manner, in part to mitigate against IFITM-mediated restriction and promote replication and transmission. This suggests therapeutic strategies that target furin-mediated cleavage of SARS-CoV-2 S may reduce viral replication through the activity of type I IFNs.IMPORTANCEThe furin cleavage site in the S protein is a distinguishing feature of SARS-CoV-2 and has been proposed to be a determinant for the higher transmissibility between individuals compared to SARS-CoV-1. One explanation for this is that it permits more efficient activation of fusion at or near the cell surface rather than requiring processing in the endosome of the target cell. Here we show that SARS-CoV-2 is inhibited by antiviral membrane protein IFITM2, and that the sensitivity is exacerbated by deletion of the furin cleavage site which restricts viral entry to low pH compartments. Furthermore, we find that IFITM2 is a significant effector of the antiviral activity of type I interferons against SARS-CoV-2 replication. We suggest one role of the furin cleavage site is to reduce SARS-CoV-2 sensitivity to innate immune restriction, and thus may represent a potential therapeutic target for COVID-19 treatment development.

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Section: Ifitm2mentioning

confidence: 99%

The polybasic cleavage site in the SARS-CoV-2 spike modulates viral sensitivity to Type I IFN and IFITM2

Winstone

Brotos

Reid

et al. 2020

Preprint

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“…Viral RNA sensing retinoic acid-inducible gene I (RIG-I) as an integral part of host pattern recognition receptors is able to detect both single and double-stranded RNAs in cytosol and initiate the primary line of defense by interferon (IFN)-mediated anti-viral response [ 25 , 51 , 52 ]. The following work shows some aspects of the SARS-Cov-2 mode of action to undermine IFN-signaling pathways [ 32 ]. Both conventional PKC-α and PKC-β are negative regulators of RIG-I.…”

Section: Inhibitory Effect Of Chelerythrine On Virus-mediated Pkc-α/-mentioning

confidence: 99%

Coronavirus disease 2019 (COVID-19), human erythrocytes and the PKC-alpha/-beta inhibitor chelerythrine –possible therapeutic implication

et al. 2020

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. Until now, diverse drugs have been used for the treatment of COVID-19. These drugs are associated with severe side effects, e.g. induction of erythrocyte death, named eryptosis. This massively affects the oxygen (O 2 ) supply of the organism. Therefore, three elementary aspects should be considered simultaneously: (1) a potential drug should directly attack the virus, (2) eliminate virus-infected host cells and (3) preserve erythrocyte survival and functionality. It is known that PKC-α inhibition enhances the vitality of human erythrocytes, while it dose-dependently activates the apoptosis machinery in nucleated cells. Thus, the use of chelerythrine as a specific PKC-alpha and -beta (PKC-α/-β) inhibitor should be a promising approach to treat people infected with SARS-CoV-2.

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“…Among them,viral ORF3b,ORF6,ORF7a,ORF7b,ORF8,ORF9b,nsp1,nsp3,nsp5,nsp6,nsp12,nsp13,nsp14,nsp15,nucleocapsid (N) and membrane (M) proteins were reported to be potential inhibitors of type I interferon production and/or type I IFN signaling pathway Konno et al, 2020;Lei et al, 2020, 2;Mu et al, 2020;Xia et al, 2020;Yuen et al, 2020). Viral ORF6 showed the most potent inhibition on IFN-β promoter and also inhibits the interferon-stimulated response element after Sendai virus infection (Lei et al, 2020, 2;Xia et al, 2020;Yuen et al, 2020). Recently, Thoms et al demonstrated the role of SARS-CoV-2 nsp1 protein in evading the immune system, including its ability to totally abrogate the ribosomal translation induced by IFN-β promoters (Thoms et al, 2020).…”

Section: Covid-19 Patients Show a Delayed Type I Interferon Responsementioning

confidence: 99%

Rationale for COVID-19 Treatment by Nebulized Interferon-β-1b–Literature Review and Personal Preliminary Experience

et al. 2020

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The inflammatory response to COVID-19 is specifically associated with an impaired type I interferon (IFN) response and complete blockade of IFN-β secretion. Clinically, nebulization of IFN-α-2b has been historically used in China to treat viral pneumonia associated with SARS-CoV. Very recent data show that the use of inhaled type I IFN is associated with decreased mortality in Chinese COVID-19 patients. However, IFN nebulization is currently not standard in Europe and the United States. Therefore, our group has set up a project aimed to evaluate the possibility to nebulize IFN-β-1b (a drug currently used in Europe to treat multiple sclerosis via subcutaneous injections) and to assess the safety of this new mode of administration in SARS-CoV-2 infected patients. We present here literature data that allowed us to build our hypothesis and to develop collaboration between clinical pharmacists, intensivists and nebulization engineers in order to gain first pre-clinical and clinical experience of IFN-β-1b nebulization. After validation of the nebulization method and verification of droplet size compatible with nebulization, the method has been applied to four intensive care patients treated at our university hospital, for whom none of the COVID-19 therapies initially used in France led to significant clinical improvement. All patients exhibited negative viral carriage and experienced clinical improvement 7–16 days after having initiated nebulized IFN-β-1b inhalation therapy. No side effects were observed. All patients were alive within a 90-days follow-up. Although it is not possible to draw firm conclusions on treatment efficacy based on this case report, our study shows that pulmonary IFN-β-1b administration is feasible, with a good safety profile. This procedure, which presents the advantage of directly targeting the lungs and reducing the risks of systemic side effects, may represent a promising therapeutic strategy for the care of patients with severe COVID-19. However, our preliminary observation requires confirmation by randomized controlled trials.

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Evasion of Type I Interferon by SARS-CoV-2

Cited by 868 publications

References 55 publications

The polybasic cleavage site in the SARS-CoV-2 spike modulates viral sensitivity to Type I IFN and IFITM2

The polybasic cleavage site in the SARS-CoV-2 spike modulates viral sensitivity to Type I IFN and IFITM2

Coronavirus disease 2019 (COVID-19), human erythrocytes and the PKC-alpha/-beta inhibitor chelerythrine –possible therapeutic implication

Rationale for COVID-19 Treatment by Nebulized Interferon-β-1b–Literature Review and Personal Preliminary Experience

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