Activation of RNase L by Murine Coronavirus in Myeloid Cells Is Dependent on BasalOasGene Expression and Independent of Virus-Induced Interferon

Abstract

The oligoadenylate synthetase (OAS)-RNase L pathway is a potent interferon (IFN)-T he coronavirus mouse hepatitis virus (MHV) strain A59 (referred to here as A59) causes moderate hepatitis and mild encephalitis, followed by chronic demyelinating disease, in susceptible C57BL/6 (B6) mice (1-3). A59 is cleared from the liver and central nervous system (CNS) primarily by the T cell response 7 to 10 days postinfection (4, 5). However, type I interferon (IFN) production, an early innate immune response, is crucial for early control of MHV infection, as mice deficient in type I IFN receptor expression (Ifnar1 Ϫ/Ϫ ) uniformly die by 2 days after infection (6-8). Interestingly, A59 fails to induce IFN-␣/␤ in most cell types, with the notable exception of myeloid cells (7). Induction of IFN-␣/␤ in macrophages and brain-resident microglia during MHV infection is dependent on sensing of viral double-stranded RNA (dsRNA) by the cytosolic RNA helicase melanoma differentiation-associated gene 5 (MDA5), encoded by Ifih1 (7, 9, 10). IFN induces a large array of interferon-stimulated genes (ISGs), which include pattern recognition receptors (PRRs), signaling molecules, transcription factors, and antiviral effectors (11)(12)(13)(14)(15)(16) (Fig. 1, left, diagrams IFN synthesis and signaling in MHV-infected macrophages). The only other source of type I IFN during A59 infection, primarily IFN-␣, is induced through a TLR7-dependent pathway in plasmacytoid dendritic cells (pDCs) (17).Among the ISGs are several Oas genes encoding proteins that function as nucleic acid sensors to synthesize 2=,5=-oligoadenylates (2-5A) in response to viral dsRNA in the host cytosol (18). Mice express several oligoadenylate synthetase (OAS) proteins that produce 2-5A, including OAS1a/g, OAS2, and OAS3, as well

Real-time 2-5A kinetics suggest that interferons β and λ evade global arrest of translation by RNase L

“…Our observations suggest that 2-5A production precedes the IFN response, and that 2-5A is supplied by basal OASs rather than by IFN-induced OASs. This model is in line with the recent report that basal OASs are sufficient and solely responsible for protecting mouse myeloid cells from murine coronavirus (39). In agreement with a key role of basally expressed OASs, we found that (i) OAS/RNase L activation is not inhibited by actinomycin D, which prevents new mRNA synthesis (SI Appendix, Fig.…”

Virus-induced inflammasome activation is suppressed by prostaglandin D 2 /DP1 signaling

“…6 F, K, and L), indicating that IFN priming is required for PGD 2 's effects. Similar requirements for IFN priming were also evident when BMMs infected with Severe Acute Respiratory Syndrome-CoV (SARS-CoV), MHV, or influenza A virus were analyzed for IFN-stimulated gene (ISG) expression (36)(37)(38)(39). PYDC3 has similarities to a family of IFN-I-inducible human proteins, which include POP1, POP2, and POP3.…”

Zika Virus Production Is Resistant to RNase L Antiviral Activity

“…Many viruses have evolved specific mechanisms and in some cases specific proteins (coronaviruses, rotaviruses, and Theiler's virus) to evade the antiviral effects of RNase L (35)(36)(37)(38)(39), which we suggest is at least in part because RNase L can be activated even while IFN signaling is antagonized (Fig. 2B) (40). Indeed, many diverse RNA (influenza virus, coronaviruses, and hepatitis C virus [HCV]) and DNA (vaccinia virus and herpesvirus) viruses antagonize the OAS-RNase L system (41), the majority of viruses targeting upstream of RNase L homodimerization and activation as effects on genome downstream of that are typically devastating to virus production.…”