Group 2 coronaviruses prevent immediate early interferon induction by protection of viral RNA from host cell recognition

Abstract

Many viruses encode antagonists to prevent interferon (IFN) induction. Infection of fibroblasts with the murine hepatitis coronavirus (MHV) and SARS-coronavirus (SARS-CoV) did not result in nuclear translocation of interferon-regulatory factor 3 (IRF3), a key transcription factor involved in IFN induction, and induction of IFN mRNA transcription. Furthermore, MHV and SARS-CoV infection could not prevent IFN induction by poly (I:C) or Sendai virus, suggesting that these CoVs do not inactivate IRF3-mediated transcription regulation, but apparently prevent detection of replicative RNA by cellular sensory molecules. Our data indicate that shielding of viral RNA to host cell sensors might be the main general mechanism for coronaviruses to prevent IFN induction.

Regulation of IRF-3-dependent Innate Immunity by the Papain-like Protease Domain of the Severe Acute Respiratory Syndrome Coronavirus

“…8C). This is consistent with two recent reports that mouse hepatitis virus and SARS-CoV do not block poly(I-C) or SeV-induced IRF-3 nuclear translocation (37,38), but it is contradictory to the fact that multiple SARSCoV proteins, including PLpro, ORF3b, ORF6, and N (35), can efficiently inhibit IRF-3 activation. The treatments used to trigger IFN response (SeV or poly(I-C) transfection) were administered at 18 h postinfection of SARS-CoV (m.o.i.…”

“…Although it is conceivable that professional IFN-producing, plasmacytoid DCs may sense single-stranded RNAs derived from SARS-CoV in endosome compartments by TLR7 and initiate an IFN response, as recently demonstrated by Cervantes-Barragan et al (73), it is currently not known whether parenchymal cells, including those from the lung epithelium, which represent the major target for SARS-CoV infection in vivo, can sense components or products of the invading SARS-CoV and initiate an innate defense response. Furthermore, it has been controversial whether SARS-CoV evades host innate immunity by simply avoiding detection by the host or has acquired mechanisms to actively block host antiviral responses (35,37,38).…”

“…1). Replication of SARS-CoV occurs within double membrane vesicles derived from endoplasmic reticulum membranes (75)(76)(77)(78), which may prevent the recognition of viral PAMPs generated during SARS-CoV replication by host PRRs (37,38). Although this evasion mechanism may contribute to the absence of IRF-3 phosphorylation early after infection, it does not explain the blockade of induction of IFN antiviral activity and the up-regulation of multiple ISG proteins that we have observed in SARS-CoV infected cells that were superinfected with SeV or transfected with poly(I-C) (Fig.…”

“…SARSCoV nsp1 was also shown to inhibit host IFN responses by inducing the degradation of host mRNAs (36). However, others have reported that infection of mouse hepatitis virus, a closely related type 2 coronavirus, or SARS-CoV does not activate IFN-␤ synthesis in murine fibroblasts nor inhibit its induction by poly(I-C) or Sendai virus (SeV) (37,38). It was proposed from these studies that group 2 coronaviruses are "invisible" to host cells and thus avoid innate immunity by somehow avoiding host recognition (37,38).…”

Type I IFN-Mediated Protection of Macrophages and Dendritic Cells Secures Control of Murine Coronavirus Infection

“…Coronaviruses, despite generation of significant amounts of type I IFN inducing dsRNA, are able to suppress early IFN-␤ induction (42,43). Furthermore, immunomodulatory nonstructural proteins (Nsp) such as Nsp1 are able to inhibit IFN-␣ responsiveness in a cell type-specific manner (31).…”