Interferon‐induced transmembrane protein 3 (IFITM3) limits lethality of SARS‐CoV‐2 in mice. (7th March 2023) - Kenney, Adam D
Abstract: Interferon‐induced transmembrane protein 3 (IFITM3) is an antiviral protein that alters cell membranes to block fusion of viruses. Conflicting reports identified opposing effects of IFITM3 on SARS‐CoV‐2 infection of cells, and its impact on viral pathogenesis in vivo remains unclear. Here, we show that IFITM3 knockout (KO) mice infected with SARS‐CoV‐2 experience extreme weight loss and lethality compared to mild infection in wild‐type (WT) mice. KO mice have higher lung viral titers and increases in inflammatory cytokine levels, immune cell infiltration, and histopathology. Mechanistically, we observe disseminated viral antigen staining throughout the lung and pulmonary vasculature in KO mice, as well as increased heart infection, indicating that IFITM3 constrains dissemination of SARS‐CoV‐2. Global transcriptomic analysis of infected lungs shows upregulation of gene signatures associated with interferons, inflammation, and angiogenesis in KO versus WT animals, highlighting changes in lung gene expression programs that precede severe lung pathology and fatality. Our results establish IFITM3 KO mice as a new animal model for studying severe SARS‐CoV‐2 infection and overall demonstrate that IFITM3 is protective in SARS‐CoV‐2 infections in vivo . Synopsis: IFITM3 limits severity of SARS‐CoV‐2 infections by restricting viral replication and spread, thereby reducing lung inflammation, immune cell infiltration, angiogenesis, and pathology. IFITM3 KO mice are a new model for studying severe SARS‐CoV‐2 infections. IFITM3 limits morbidity and mortality following SARS‐CoV‐2 infection in two mouse models. Enhanced viral replication in IFITM3 KO mice is accompanied by increased lung pathology and extrapulmonary virus dissemination. IFITM3 KO mice upregulate inflammatory, angiogenic, and pro‐thrombotic gene programs following SARS‐CoV‐2 infection. IFITM3 KO mice provide a tool for studying severe SARS‐CoV‐2 infections with likely relevance to human populations with IFITM3 deficiencies. Abstract : IFITM3 limits severity of SARS‐CoV‐2 infections by restricting viral replication and spread, thereby reducing lung inflammation, immune cell infiltration, angiogenesis, and pathology. IFITM3 KO mice are a new model for studying severe SARS‐CoV‐2 infections.