Coronaviruses (CoVs) encode multiple
interferon (IFN) antagonists that modulate the host response to virus replication. Here, we evaluated the host transcriptional response to
infection with murine coronaviruses encoding independent mutations in one of two different viral antagonists, the
deubiquitinase (DUB) within nonstructural
protein 3 or the
endoribonuclease (
EndoU) within nonstructural
protein 15. We used transcriptomics approaches to compare the scope and kinetics of the host response to the wild-type (WT), DUBmut, and EndoUmut viruses in infected macrophages. We found that the EndoUmut virus activates a focused response that predominantly involves
type I interferons and
interferon-related genes, whereas the WT and DUBmut viruses more broadly stimulate upregulation of over 2,800 genes, including networks associated with activating the unfolded protein response (UPR) and the proinflammatory response associated with viral pathogenesis. This study highlights the role of viral
interferon antagonists in shaping the kinetics and magnitude of the host response during
virus infection and demonstrates that inactivating a dominant viral antagonist, the coronavirus
endoribonuclease, dramatically alters the host response in macrophages.IMPORTANCE Macrophages are an important cell type during
coronavirus infections because they "notice" the
infection and respond by inducing
type I interferons, which limits virus replication. In turn, coronaviruses encode
proteins that mitigate the cell's ability to signal an
interferon response. Here, we evaluated the host macrophage response to two independent mutant coronaviruses, one with reduced deubiquitinating activity (DUBmut) and the other containing an inactivated
endoribonuclease (EndoUmut). We observed a rapid, robust, and focused response to the EndoUmut virus, which was characterized by enhanced expression of
interferon and
interferon-related genes. In contrast, wild-type virus and the DUBmut virus elicited a more limited
interferon response and ultimately activated over 2,800 genes, including players in the unfolded protein response and proinflammatory pathways associated with progression of significant disease. This study reveals that
EndoU activity substantially contributes to the ability of coronaviruses to evade the host innate response and to replicate in macrophages.