Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA.
Infectious Diseases Institute, The Ohio State University, Columbus, OH, USA.
EMBO Rep. 2023 Apr 5;24(4):e56660. doi: 10.15252/embr.202256660. Epub 2023 Mar 7.
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.
干扰素诱导跨膜蛋白 3（IFITM3）是一种抗病毒蛋白，可改变细胞膜以阻止病毒融合。有相互矛盾的报道指出 IFITM3 对 SARS-CoV-2 感染细胞的作用相反，其对体内病毒发病机制的影响尚不清楚。在这里，我们发现感染 SARS-CoV-2 的 IFITM3 敲除（KO）小鼠与野生型（WT）小鼠的轻度感染相比，体重减轻和死亡率极高。KO 小鼠的肺部病毒滴度更高，促炎细胞因子水平、免疫细胞浸润和组织病理学增加。从机制上看，我们观察到 KO 小鼠的肺部和肺血管中弥漫性病毒抗原染色，以及心脏感染增加，表明 IFITM3 限制了 SARS-CoV-2 的传播。感染肺部的全基因组转录组分析显示，与 WT 动物相比，KO 动物中与干扰素、炎症和血管生成相关的基因特征上调，突出了严重肺部病理和死亡之前肺基因表达程序的变化。我们的结果确立了 IFITM3 KO 小鼠作为研究严重 SARS-CoV-2 感染的新动物模型，并证明 IFITM3 在体内 SARS-CoV-2 感染中具有保护作用。
