Parsing the roles of innate and adaptive immunity in lethal, type I interferon-driven, immunopathological disease in LCMV-infected STAT KO mice

Abstract

Type I interferons (IFN-I) have paradoxical roles in immune responses. While being key mediators of host responses to infectious agents and immunomodulators of innate and adaptive immunity through activation of interferon-stimulated gene factor 3 (ISGF3), a complex of STAT1, STAT2 and IRF9, these cytokines have pathological roles in autoinflammatory disorders. In parallel to the canonical signaling pathway, many reports highlight the pathophysiological roles of non-ISGF3, alternative IFN-I signaling pathways. Previously, the Campbell lab showed that unlike WT mice, STAT1 knock-out (KO) mice develop STAT2 and IRF9-dependent, IFN I dependent, CD4+ T-cell-mediated, lethal wasting disease following infection with a largely non cytopathic virus, lymphocytic choriomeningitis virus (LCMV). However, the molecular and cellular mechanisms by which the lethal disease is mediated in LCMV-infected STAT1 KO mice remain to be fully investigated. Based on the work in this project, we proposed a model of biphasic disease mediated by STAT1-independent, alternative IFN I signaling in these mice. The early phase involved innate immunity-driven, strong but transient IFN I production and IFN I-dependent, exaggerated, inflammatory responses. The late phase involved adaptive immunity-mediated, amplified, inflammatory responses. We showed that the combinatorial effects of these two phases are necessary for the lethal wasting disease in LCMV-infected STAT1 KO mice, as the ablation of the former by blocking IFN I signaling (STAT1/IFNAR double KO mice) or the latter by removing mature adaptive immune cells (STAT1/RAG1 double KO mice) prevented the death of the mice. These findings provide insight into the complex molecular and cellular requirements that determine whether IFN I play beneficial or detrimental roles during viral infection. Specifically, these findings further elucidate the pathophysiological roles of ISGF3-independent, alternative IFN I signaling during viral infection.