Type I interferon receptor-independent and -dependent host transcriptional responses to mouse hepatitis coronavirus infection in vivo

Abstract

BackgroundThe role of type I IFNs in protecting against coronavirus (CoV) infections is not fully understood. While CoVs are poor inducers of type I IFNs in tissue culture, several studies have demonstrated the importance of the type I IFN response in controlling MHV infection in animals. The protective effectors against MHV infection are, however, still unknown.ResultsIn order to get more insight into the antiviral gene expression induced in the brains of MHV-infected mice, we performed whole-genome expression profiling. Three different mouse strains, differing in their susceptibility to infection with MHV, were used. In BALB/c mice, which display high viral loads but are able to control the infection, 57 and 121 genes were significantly differentially expressed (≥ 1.5 fold change) upon infection at 2 and 5 days post infection, respectively. Functional association network analyses demonstrated a strong type I IFN response, with Irf1 and Irf7 as the central players. At 5 days post infection, a type II IFN response also becomes apparent. Both the type I and II IFN response, which were more pronounced in mice with a higher viral load, were not observed in 129SvEv mice, which are much less susceptible to infection with MHV. 129SvEv mice lacking the type I interferon receptor (IFNAR-/-), however, were not able to control the infection. Gene expression profiling of these mice identified type I IFN-independent responses to infection, with IFN-γ as the central player. As the BALB/c and the IFNAR-/- 129SvEv mice demonstrated very similar viral loads in their brains, we also compared their gene expression profiles upon infection with MHV in order to identify type I IFN-dependent transcriptional responses. Many known IFN-inducible genes were detected, several of which have previously been shown to play an important protective role against virus infections. We speculate that the additional type I IFN-dependent genes that we discovered may also be important for protection against MHV infection.ConclusionTranscriptional profiling of mice infected with MHV demonstrated the induction of a robust IFN response, which correlated with the viral load. Profiling of IFNAR-/- mice allowed us to identify type I IFN-independent and -dependent responses. Overall, this study broadens our present knowledge of the type I and II IFN-mediated effector responses during CoV infection in vivo.

Analysis of the cumulative changes in Graves’ disease thyroid glands points to IFN signature, plasmacytoid DCs and alternatively activated macrophages as chronicity determining factors

“…4A and Supplementary Table S2). However, not all the genes typically associated with type 1 IFN signature response to virus, such as MX1, MX2, UBE1L, ISGF3, IRF1, IRF3 or IRF7 [45], were strongly induced in our studies. In addition many of the most differentially expressed genes were downstream of IFNs' receptors.…”

The type I interferon response bridles rabies virus infection and reduces pathogenicity

“…However, it may be inappropriate to compare the kinetic of death in IFNAR −/− and NesCre ( +/− ) IFNAR ( flox/flox ) mice since the two types of mice do not have the same genetic background. To note and as already reported in other viral infections (Raaben et al 2009), susceptibility of 129/S2/Sv to RABV was reduced (25% mortality) compared to C57BL6 mice (50% mortality), making difficult the comparison of RABV infection in IFNAR −/− and NesCre ( +/− ) IFNAR ( flox/flox ) mice.…”

Accessory Protein 5a Is a Major Antagonist of the Antiviral Action of Interferon against Murine Coronavirus

“…A number of additional ISG products with antiviral activity have been described and characterized to various extents, including ISG15, ISG20, MxA, ADAR1, viperin, and tetherin (19,33,40,43); some of them have been found to be upregulated in MHV-infected mice (32). It remains to be determined which of these factors can exert significant control over MHV infections, either in immortalized cell lines or in primary cells (35), and whether all coronaviruses will turn out to be sensitive to the same subset of ISGs.…”