Insights into pandemic respiratory viruses: manipulation of the antiviral interferon response by SARS-CoV-2 and influenza A virus

Abstract

The outbreak of the COVID-19 pandemic one year after the centennial of the 1918 influenza pandemic reaffirms the catastrophic impact respiratory viruses can have on global health and economy. A key feature of SARS-CoV-2 and influenza A viruses (IAV) is their remarkable ability to suppress or dysregulate human immune responses. Here, we summarize the growing knowledge about the interplay of SARS-CoV-2 and antiviral innate immunity, with an emphasis on the regulation of type-I or -III interferon responses that are critically implicated in COVID-19 pathogenesis. Furthermore, we draw parallels to IAV infection and discuss shared innate immune sensing mechanisms and the respective viral countermeasures.

Figure 1

Induction and antagonism of type-I/-III IFN responses by SARS-CoV-2 and IAV. Type-I/-III IFN induction by SARS-CoV-2 relies primarily on MDA5, which senses long dsRNA species. MDA5 then undergoes a series of PTMs, including ISGylation in its caspase activation and recruitment domains (CARDs), oligomerizes, and translocates to the mitochondrion where it interacts with and activates MAVS. MAVS recruits downstream signaling molecules such as TBK1/IKKε and the IKKα/β/γ complex that subsequently activate transcription factors, including IRF3 and NF-κB. Upon translocation from the cytoplasm to the nucleus, these transcription factors drive the expression of type-I/-III IFNs and proinflammatory cytokines, which, once secreted, prompt autocrine and paracrine signaling in infected and bystander cells, respectively. Specifically, type-I/-III IFNs engage cognate IFN receptors that signal through the JAK–STAT axis to upregulate ISGs. Besides MDA5, the cGAS–STING pathway (via released mtDNA), as well as TLR3 and TLR7, are also implicated in SARS-CoV-2 sensing possibly in a cell-type-specific manner, though the mechanistic details require further investigation. These sensing pathways activate similar downstream kinases and transcription factors, leading to type-I/-III IFN gene expression. A prenylated OAS1 isoform, which anchors to the endoplasmic reticulum-derived double-membrane vesicles (DMVs) where SARS-CoV-2 replication takes place, restricts virus replication by activating RNase L. RIG-I exerts an IFN-independent restriction mechanism by competing with the SARS-CoV-2 polymerase for binding to the 3′-UTR of the viral genome (not depicted). Likewise, during IAV infection, RIG-I binds to the genomic RNA panhandle region associated with the IAV polymerase, which can impede viral replication in an IFN-independent manner (not illustrated). In many cell types (except plasmacytoid dendritic cells for example), IFN induction by IAV is primarily or exclusively dependent on RIG-I. Upon recognition of the IAV (sub)genomic panhandle structure, RIG-I undergoes conformational changes and PTMs such as activating K63-linked polyubiquitination in its CARDs and C-terminal domain (CTD) by TRIM25 and Riplet, respectively. RIG-I then activates an analogous signaling pathway as MDA5 to induce antiviral immunity. To evade immune surveillance, IAV uses the NS1 protein as the primary IFN antagonist. NS1 binds to TRIM25 and Riplet, thereby inhibiting the K63-linked polyubiquitination of RIG-I in the cytoplasm. NS1 also localizes to the nucleus where it blocks polyadenylation and nuclear export of cellular mRNAs via binding to the cellular cleavage and polyadenylation factor 30 (CPSF30). This host-shutoff strategy is believed to act in concert with another host-shutoff mechanism carried out by IAV PA-X protein, which selectively degrades host RNA polymerase II (Pol II) transcripts via its endonucleolytic activity. The IAV PB1–F2 protein binds to MAVS at the mitochondrion and suppresses MAVS activation by decreasing the mitochondrial membrane potential. Like IAV, SARS-CoV-2 targets critical PTMs of innate sensors and downstream signaling molecules to antagonize IFN responses. The PLpro activity of Nsp3 actively removes conjugated ISG15 from MDA5 and IRF3 to suppress their activation. Furthermore, extracellular secretion of free ISG15 prompted by PLpro’s de-ISGylating activity can exacerbate proinflammatory cytokine responses. Nsp5 cleaves and disables RIG-I and also induces MAVS degradation. Nsp1 plugs the mRNA entry tunnel of the 40S ribosomal subunit to shut off host-protein translation. Nsp14 and Nsp16 also reportedly disturb host translation and transcription processes, though the precise mechanisms are still unknown. Nsp14 and Nsp16 catalyze Cap-1 modification of viral RNA to mimic host mRNA and escape recognition by MDA5. Nsp15 of murine hepatitis virus and likely also SARS-CoV-2 cleaves and limits the accumulation of viral dsRNA to evade MDA5 sensing. Orf9b competes with the chaperone protein Hsp90 for binding to TOM70 and thereby impairs the recruitment of TBK1 and IRF3 (both associated with Hsp90) to the TOM70–MAVS complex. Orf6 interacts with the nuclear pore complex Nup98–Rae1 and impedes the nuclear import of IRF3 and STAT1/2. Orf3a, Orf7a/b, M, and N also reportedly dampen STAT1/2 and/or MAVS activation; the underlying mechanisms, however, require further investigation. SARS-CoV-2 proteins inhibiting IFN/ISG responses are depicted in pink. IAV proteins blocking innate immune signaling are illustrated in orange. ‘Ub’ indicates ubiquitin.