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dc.contributor.authorPage, C.
dc.contributor.authorGoicochea, L.
dc.contributor.authorMatthews, K.
dc.contributor.authorFrieman, M.
dc.date.accessioned2020-03-27T15:13:17Z
dc.date.available2020-03-27T15:13:17Z
dc.date.issued2012
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84870726220&doi=10.1128%2fJVI.01689-12&partnerID=40&md5=3dbf63591f8d0a3c540f64e7b1242f3b
dc.identifier.urihttp://hdl.handle.net/10713/12423
dc.description.abstractInfection with severe acute respiratory syndrome coronavirus (SARS-CoV) causes acute lung injury (ALI) that often leads to severe lung disease. A mouse model of acute SARS-CoV infection has been helpful in understanding the host response to infection; however, there are still unanswered questions concerning SARS-CoV pathogenesis. We have shown that STAT1 plays an important role in the severity of SARS-CoV pathogenesis and that it is independent of the role of STAT1 in interferon signaling. Mice lacking STAT1 have greater weight loss, severe lung pathology with pre-pulmonary-fibrosis-like lesions, and an altered immune response following infection with SARS-CoV. We hypothesized that STAT1 plays a role in the polarization of the immune response, specifically in macrophages, resulting in a worsened outcome. To test this, we created bone marrow chimeras and celltype- specific knockouts of STAT1 to identify which cell type(s) is critical to protection from severe lung disease after SARS-CoV infection. Bone marrow chimera experiments demonstrated that hematopoietic cells are responsible for the pathogenesis in STAT1-/- mice, and because of an induction of alternatively activated (AA) macrophages after infection, we hypothesized that the AA macrophages were critical for disease severity. Mice with STAT1 in either monocytes and macrophages (LysM/STAT1) or ciliated lung epithelial cells (FoxJ1/STAT1) deleted were created. Following infection, LysM/STAT1 mice display severe lung pathology, while FoxJ1/STAT1 mice display normal lung pathology. We hypothesized that AA macrophages were responsible for this STAT1-dependent pathology and therefore created STAT1/STAT6-/- double-knockout mice. STAT6 is essential for the development of AA macrophages. Infection of the double-knockout mice displayed a lack of lung disease and prefibrotic lesions, suggesting that AA macrophage production may be the cause of STAT1-dependent lung disease. We propose that the control of AA macrophages by STAT1 is critical to regulating immune pathologies and for protection from long-term progression to fibrotic lung disease in a mouse model of SARS-CoV infection.en_US
dc.description.urihttps://doi.org/10.1128/JVI.01689-12en_US
dc.language.isoen_USen_US
dc.relation.ispartofJournal of Virology
dc.subjectsevere acute respiratory syndrome coronavirusen_US
dc.subjectSARS-CoVen_US
dc.subjectpathogenesisen_US
dc.subjectalternatively activated macrophagesen_US
dc.subject.meshSARS Virusen_US
dc.subject.meshMacrophagesen_US
dc.subject.meshSTAT1 Transcription Factoren_US
dc.subject.meshCoronavirus infectionsen_US
dc.subject.meshMiceen_US
dc.titleInduction of alternatively activated macrophages enhances pathogenesis during severe acute respiratory syndrome coronavirus infectionen_US
dc.typeArticleen_US
dc.identifier.doi10.1128/JVI.01689-12
dc.identifier.pmid23015710
dc.identifier.ispublishedNo


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