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

Background: The 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.
Results: In order to get more insight into the antiviral gene expression induced in the brains of MHVinfected 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 IFNdependent genes that we discovered may also be important for protection against MHV infection.
Conclusion: Transcriptional 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