Browsing School, Graduate by Subject "SARS Virus"
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Overactive EGFR Signaling Leads to Lung Fibrosis After SARS-CoV InfectionSARS coronavirus (SARS-CoV) is a pathogenic respiratory virus that causes acute lung injury in humans. In turn, the host mounts a wound healing response to repair the injury. One of the major sequelae caused by SARS-CoV is pulmonary fibrosis (PF), which occurs more frequently in older patients. Fibrosis is caused by a dysregulated wound healing response and the molecular pathways underlying the development of fibrosis are not completely understood. Using mouse models of SARS-CoV pathogenesis, we have identified that the wound healing pathway, controlled by the epidermal growth factor receptor (EGFR) is critical to recovery from SARS-CoV induced tissue damage. In mice with constitutively active EGFR, [EGFR(DSK5) mice], we find that SARS-CoV infection causes enhanced lung disease. Importantly, we show that during infection the EGFR ligands amphiregulin and HB-EGF are upregulated and exogenous addition of these ligands during infection of wildtype mice leads to enhanced lung disease and altered wound healing dynamics. Our data demonstrate a key role of EGFR in the host response to SARS-CoV and how it may be implicated in lung disease induced by other highly pathogenic respiratory viruses.
The Role of STAT1 in SARS Coronavirus PathogenesisInfection 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.