Canonical type I interferon (IFN-I) signaling through interferon stimulated gene factor (ISGF) 3 has a key role in host innate and adaptive immune responses during viral infection. We have previously found that following systemic infection with lymphocytic choriomeningitis virus (LCMV), STAT1 KO but not WT, IFNAR KO or STAT1/IFNAR DKO mice develop lethal disease characterized by a ‘cytokine storm’. Furthermore, CD4+ T cells were shown to be perpetrators of this lethal phenotype. This study aims to determine the underlying molecular mechanisms of this lethal disease. As an in vitro model of antigen presenting cells (APCs), bone marrow-derived macrophages (BMDMs) from WT, STAT1 KO, IFNAR KO and STAT1/IFNAR DKO were infected with LCMV. The induction of ISG15 mRNA was significantly higher in infected WT BMDMs compared with the other genotypes, consistent with the loss of a canonical anti-viral response in the absence of STAT1 and/or IFNAR. In contrast, infected STAT1 KO, IFNAR KO and STAT1/IFNAR DKO BMDMs showed comparably increased mRNA levels for various pro-inflammatory cytokines (e.g. IL-6 and IL-1β). Furthermore, phosphorylation of STAT3, STAT6, NFκB and ERK was increased in infected BMDMs independent of the genotype. However, pY-STAT2 induction was only observed in infected WT BMDMs.  The activation of these signaling molecules was also observed in liver and kidney extracts from LCMV-infected WT, STAT1 KO, IFNAR KO and STAT1/IFNAR DKO mice. In particular, activation of STAT2 was found in WT and STAT1 KO mice only and pY-STAT2 levels were significantly higher in the absence of STAT1 during infection.  These studies show that LCMV infection in BMDMs and in vivo induces: 1) a core host response that is independent of IFN-I, and 2) a non-canonical STAT1-independent IFN-I-dependent signaling response.