Restriction of Viral Membrane Fusion and Entry by IFITM Proteins

描述（由申请人提供）：我们研究的长期目标是更好地了解病毒进入的机制以及可能对治疗干预的影响。为了实现这些目标，我们最近研究了干扰素诱导的跨膜（IFITM）蛋白，该蛋白能有效抑制多种病毒的侵入和感染，包括高致病性甲型流感病毒（IAV）、SARS冠状病毒、埃博拉病毒（EBOV）和HIV-1病毒。我们发现IFITM蛋白能深度抑制IAV HA、塞姆利基森林病毒（SFV） E1和水疱性口炎病毒（VSV） G蛋白诱导的细胞-细胞融合，这三种蛋白分别代表I类、II类和III类病毒融合蛋白。进一步的实验表明，IFITMs阻断了病毒膜半灌注的产生，这与它们降低膜流动性的能力是一致的。有趣的是，我们观察到一些病毒对特定类型的ifitm的抑制比其他病毒更敏感，这表明

DESCRIPTION (provided by applicant): The long-term objective of our research is to better understand the mechanisms of viral entry and the possible implications for therapeutic interventions. To achieve these goals, we have recently studied the interferon-inducible transmembrane (IFITM) proteins that potently inhibit entry and infection of a wide range of viruses, including those of the highly pathogenic influenza A virus (IAV), SARS coronavirus, Ebolavirus (EBOV), and HIV-1. We showed that IFITM proteins profoundly inhibit cell-cell fusion induced by IAV HA, Semliki Forest virus (SFV) E1, and vesicular stomatitis virus (VSV) G proteins, which represent class I, II and III viral fusion proteins, respectively. Further experiments revealed that IFITMs block the creation of viral membrane hemifusion, which is consistent with their ability to decrease membrane fluidity. Interestingly, we observed that some viruses are more sensitive than others to inhibition by particular types of IFITMs, suggesting that IFITM-mediated restriction of viral entry can, in addition to broad inhibitions, be virus dependent The specific aims of this project are (1) to determine the molecular and biophysical mechanisms by which IFITMs inhibit viral membrane fusion, (2) to understand the molecular basis by which IFITM proteins change lipid properties and membrane mechanics, thereby inhibiting viral membrane fusion, and (3) to elucidate the molecular and cellular control mechanisms that govern the differential antiviral activities of IFITMs. Collectively, understanding the underlying mechanisms of IFITMs as proposed in this work will significantly advance our knowledge of IFN-mediated intrinsic immunity against viral entry. Results from the proposed experiments will aid the development of novel therapeutic agents against viral infections.