Department of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America.
PLoS Pathog. 2011 Jan 6;7(1):e1001258. doi: 10.1371/journal.ppat.1001258.
Interferon-inducible transmembrane proteins 1, 2, and 3 (IFITM1, 2, and 3) are recently identified viral restriction factors that inhibit infection mediated by the influenza A virus (IAV) hemagglutinin (HA) protein. Here we show that IFITM proteins restricted infection mediated by the entry glycoproteins (GP(1,2)) of Marburg and Ebola filoviruses (MARV, EBOV). Consistent with these observations, interferon-β specifically restricted filovirus and IAV entry processes. IFITM proteins also inhibited replication of infectious MARV and EBOV. We observed distinct patterns of IFITM-mediated restriction: compared with IAV, the entry processes of MARV and EBOV were less restricted by IFITM3, but more restricted by IFITM1. Moreover, murine Ifitm5 and 6 did not restrict IAV, but efficiently inhibited filovirus entry. We further demonstrate that replication of infectious SARS coronavirus (SARS-CoV) and entry mediated by the SARS-CoV spike (S) protein are restricted by IFITM proteins. The profile of IFITM-mediated restriction of SARS-CoV was more similar to that of filoviruses than to IAV. Trypsin treatment of receptor-associated SARS-CoV pseudovirions, which bypasses their dependence on lysosomal cathepsin L, also bypassed IFITM-mediated restriction. However, IFITM proteins did not reduce cellular cathepsin activity or limit access of virions to acidic intracellular compartments. Our data indicate that IFITM-mediated restriction is localized to a late stage in the endocytic pathway. They further show that IFITM proteins differentially restrict the entry of a broad range of enveloped viruses, and modulate cellular tropism independently of viral receptor expression.
干扰素诱导跨膜蛋白 1、2 和 3（IFITM1、2 和 3）是最近发现的病毒限制因子，可抑制流感 A 病毒（IAV）血凝素（HA）蛋白介导的感染。在这里，我们表明 IFITM 蛋白限制了马尔堡病毒和埃博拉病毒（MARV、EBOV）进入糖蛋白（GP(1,2)）介导的感染。与这些观察结果一致，干扰素-β 特异性限制了丝状病毒和 IAV 的进入过程。IFITM 蛋白也抑制了传染性 MARV 和 EBOV 的复制。我们观察到 IFITM 介导的限制的不同模式：与 IAV 相比，MARV 和 EBOV 的进入过程受 IFITM3 的限制较小，但受 IFITM1 的限制较大。此外，鼠源 Ifitm5 和 6 不限制 IAV，但能有效抑制丝状病毒的进入。我们进一步证明，传染性 SARS 冠状病毒（SARS-CoV）的复制和由 SARS-CoV 刺突（S）蛋白介导的进入受 IFITM 蛋白的限制。IFITM 蛋白对 SARS-CoV 的限制模式与丝状病毒更为相似，而不是与 IAV。受体相关的 SARS-CoV 假病毒的胰蛋白酶处理，绕过了对溶酶体组织蛋白酶 L 的依赖，也绕过了 IFITM 介导的限制。然而，IFITM 蛋白并没有降低细胞组织蛋白酶的活性，也没有限制病毒颗粒进入酸性细胞内区室。我们的数据表明，IFITM 介导的限制局限于内体途径的晚期。它们进一步表明，IFITM 蛋白可差异限制广泛包膜病毒的进入，并独立于病毒受体表达调节细胞嗜性。
