Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio.
Infectious Diseases Institute, The Ohio State University, Columbus, Ohio.
J Infect Dis. 2018 Oct 5;218(10):1582-1591. doi: 10.1093/infdis/jiy361.
Human metapneumovirus (hMPV) utilizes a bifurcated cellular entry strategy, fusing either with the plasma membrane or, after endocytosis, with the endosome membrane. Whether cellular factors restrict or enhance either entry pathway is largely unknown. We found that the interferon-induced transmembrane protein 3 (IFITM3) inhibits hMPV infection to an extent similar to endocytosis-inhibiting drugs, and an IFITM3 variant that accumulates at the plasma membrane in addition to its endosome localization provided increased virus restriction. Mechanistically, IFITM3 blocks hMPV F protein-mediated membrane fusion, and inhibition of infection was reversed by the membrane destabilizing drug amphotericin B. Conversely, we found that infection by some hMPV strains is enhanced by the endosomal protein toll-like receptor 7 (TLR7), and that IFITM3 retains the ability to restrict hMPV infection even in cells expressing TLR7. Overall, our results identify IFITM3 as an endosomal restriction factor that limits hMPV infection of cells.
人偏肺病毒（hMPV）利用分叉的细胞进入策略，与质膜融合或内吞作用后与内体膜融合。细胞因子是否限制或增强任一进入途径在很大程度上尚不清楚。我们发现干扰素诱导跨膜蛋白 3（IFITM3）在一定程度上抑制 hMPV 感染，其抑制效果与内吞作用抑制剂相似，并且在其定位于内体的基础上积累在质膜上的 IFITM3 变体可增加病毒限制。从机制上讲，IFITM3 阻断 hMPV F 蛋白介导的膜融合，并且感染抑制可被膜破坏药物两性霉素 B 逆转。相反，我们发现一些 hMPV 株的感染可被内体蛋白 Toll 样受体 7（TLR7）增强，并且 IFITM3 即使在表达 TLR7 的细胞中也保留限制 hMPV 感染的能力。总的来说，我们的结果表明 IFITM3 是一种限制 hMPV 感染细胞的内体限制因子。
