The Role of STAT1 in SARS Coronavirus Pathogenesis

Abstract

Infection with Severe acute respiratory syndrome Coronavirus (SARS-CoV) often caused severe end stage lung disease with characteristics of acute lung injury, especially in elderly populations. The virus-host interactions that govern this severe response are not well understood. We have previously shown that STAT1 signaling plays an important role in control of SARS-CoV pathogenesis and this control is independent of the role of STAT1 in interferon signaling. STAT1-/- mice have greater weight loss, worsened lung pathology and an altered immune response consisting of elevated Alternatively activated macrophages (AAMs) following infection with SARS-CoV. We hypothesized that STAT1 is playing a role in the polarization of the immune response, specifically in macrophages, resulting in a worsened outcome and long-term lung disease. To test this hypothesis, we first created bone marrow chimeras to determine the lineage of cells that contributes to the enhanced pathology when STAT1 is deleted. Upon histological examination, mice lacking STAT1 in cells of the hematopoietic lineage display more severe lung pathology following infection with a mouse adapted SARS-CoV (rMA15). In order to examine the contribution of the macrophage population to SARS-CoV pathogenesis, we developed a conditional knockout strain of mice utilizing the LysM promoter to delete STAT1 in monocytes and macrophages. Following infection with SARS-CoV, LysM/STAT1 mice have a delay in viral clearance and enhanced lung pathology characterized by enhanced fibroblast proliferation as well as numerous lymphoid aggregates at 9 days post-infection. This pathology is suggestive of a pre-fibrotic state, which has been observed in some human patients following SARS-CoV infection. Induction of AAMs was blocked through concurrent deletion of STAT6 with STAT1, which successfully ameliorated the enhanced disease phenotype. These double deleted mice displayed very limited pathology following infection. STAT1-/- mice were also studied at 21 days post-infection to evaluate long-term effects of SARS-CoV infection. STAT1-/- mice maintained more severe lung pathology at this late time point, displayed continued presence of AAM-associated proteins and increased levels of activated collagen. We propose that STAT1 is important in controlling macrophage activation and polarization during SARS-CoV infection in order to help limit immune mediated pathologies and long-term progression to fibrotic disease.