IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes

Channappanavar, Rudragouda; Fehr, Anthony R.; Zheng, Jin; Wohlford‐Lenane, Christine L.; Abrahante, Juan E.; Mack, Matthias; Sompallae, Ramakrishna; McCray, Paul B.; Meyerholz, David K.; Perlman, Stanley

doi:10.1172/jci126363

Cited by 518 publications

(641 citation statements)

References 71 publications

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“…However, SARS-CoV and MERS-CoV can induce the production of double-membrane vesicles that lack PRRs and then replicate in these vesicles, thereby avoiding the host detection of their dsRNA [39]. [40,41]. Accessory protein 4a of MERS-CoV may block the induction of IFN at the level of MDA5 activation through direct interaction with double-stranded RNA [42].…”

Section: Coronavirus Immune Evasionmentioning

confidence: 99%

Molecular immune pathogenesis and diagnosis of COVID-19

Geng

Peng

et al. 2020

Journal of Pharmaceutical Analysis

1,489

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Section: Coronavirus Immune Evasionmentioning

confidence: 99%

Molecular immune pathogenesis and diagnosis of COVID-19

Geng

Peng

et al. 2020

Journal of Pharmaceutical Analysis

1,489

1,641

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“…However, this effect is insufficient to decrease ARDS mortality (Ranieri et al, 2020). It has been suggested from in vivo studies in mice that the timing of IFN-I administration plays a crucial role: positive effects were observed if IFN-I was administered shortly after infection, but IFN-I failed to inhibit viral replication and had side-effects when administered later (Channappanavar et al, 2019). Following a study showing that IFNβ1b was as efficient as lopinavir/ritonavir against MERS-CoV in marmosets (Chan et al, 2015), the combination of IFNβ1b (injected intravenously) and lopinavir/ritonavir is currently investigated in a clinical trial in Saudi Arabia (Arabi et al, 2018).…”

Section: Main Textmentioning

confidence: 99%

“…From the data presented above, IFN-I might be a safe and efficient treatment against SARS-CoV-2. Knowledge acquired during studies on MERS-CoV or SARS-CoV would be critical assets in that perspective: for example, they indicate that IFNβ should be the most relevant interferon subtype, and that IFN-I should be administered as early as possible to optimize antiviral therapy and avoid adverse events (Channappanavar et al, 2019). Furthermore, COVID-19 pathology, mainly consisting in pulmonary lesions, presents similar characteristics with interferonopathies: it may suggest that SARS-CoV-2 induces an excessive IFN-I mediated antiviral response, leading to tissue damage.…”

Section: Main Textmentioning

confidence: 99%

Type 1 interferons as a potential treatment against COVID-19

et al. 2020

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“…Other host dsRNA PRRs, such as PKR and OAS, are also activated and operate to limit CoV replication (7)(8)(9)(10)(11). CoVs encode multiple proteins that antagonize these innate immune responses, particularly the activation of the IFN response (9,(12)(13)(14)(15)(16), ultimately leading to a dysregulated immune response and increased immunopathogenesis (17,18). Understanding the mechanisms used by CoVs to delay IFN signaling may provide opportunities for the development of antivirals and live-attenuated vaccines to limit CoV infections.…”

mentioning

confidence: 99%

Coronavirus endoribonuclease targets viral polyuridine sequences to evade activating host sensors

Hackbart

Deng

Baker

2020

Proc. Natl. Acad. Sci. U.S.A.

263

265

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Coronaviruses (CoVs) are positive-sense RNA viruses that can emerge from endemic reservoirs and infect zoonotically, causing significant morbidity and mortality. CoVs encode an endoribonuclease designated EndoU that facilitates evasion of host pattern recognition receptor MDA5, but the target of EndoU activity was not known. Here, we report that EndoU cleaves the 5′-polyuridines from negative-sense viral RNA, termed PUN RNA, which is the product of polyA-templated RNA synthesis. Using a virus containing an EndoU catalytic-inactive mutation, we detected a higher abundance of PUN RNA in the cytoplasm compared to wildtype−infected cells. Furthermore, we found that transfecting PUN RNA into cells stimulates a robust, MDA5-dependent interferon response, and that removal of the polyuridine extension on the RNA dampens the response. Overall, the results of this study reveal the PUN RNA to be a CoV MDA5-dependent pathogen-associated molecular pattern (PAMP). We also establish a mechanism for EndoU activity to cleave and limit the accumulation of this PAMP. Since EndoU activity is highly conserved in all CoVs, inhibiting this activity may serve as an approach for therapeutic interventions against existing and emerging CoV infections.C oronaviruses (CoVs) are positive-sense RNA viruses that replicate in the cytoplasm of infected cells. The positivesense virion RNA is translated to generate the viral replication machinery, which then replicates the positive-sense RNA into negative-sense, genomic RNA and subgenomic RNAs (sgRNAs). The negative-sense RNAs then function as templates for synthesis of positive-sense genomic RNA and sgRNA (1, 2). This replication strategy can generate long double-stranded RNA (dsRNA) intermediates (3), that may act as pathogen-associated molecular patterns (PAMPs) recognized by cytoplasmic pattern recognition receptors (PRRs) (4, 5). The specific PRR that recognizes CoV RNA is MDA5, which can activate the type I interferon (IFN) response in macrophages (6). Other host dsRNA PRRs, such as PKR and OAS, are also activated and operate to limit CoV replication (7-11). CoVs encode multiple proteins that antagonize these innate immune responses, particularly the activation of the IFN response (9, 12-16), ultimately leading to a dysregulated immune response and increased immunopathogenesis (17,18). Understanding the mechanisms used by CoVs to delay IFN signaling may provide opportunities for the development of antivirals and live-attenuated vaccines to limit CoV infections.Here, we investigate the mechanism used by one CoV IFN antagonist, the nonstructural protein 15 (nsp15), which is an endoribonuclease designated EndoU. EndoU is highly conserved in all known CoVs (19,20). EndoU is similar to the cellular endoribonuclease XendoU, as revealed by bioinformatic analysis of the amino acid sequence (21). X-ray structures of EndoU revealed conserved endoribonuclease folds with catalytic histidine residues required for endoribonuclease activity (22)(23)(24)(25)(26). Purified EndoU was shown to cleave single-str...

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IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes

Cited by 518 publications

References 71 publications

Molecular immune pathogenesis and diagnosis of COVID-19

Molecular immune pathogenesis and diagnosis of COVID-19

Type 1 interferons as a potential treatment against COVID-19

Coronavirus endoribonuclease targets viral polyuridine sequences to evade activating host sensors

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