The Interferon-Stimulated GeneIfitm3Restricts West Nile Virus Infection and Pathogenesis

Abstract

T he interferon (IFN)-induced transmembrane protein (IFITM) genes consist of a family of genes encoding related proteins: Ifitm1,2,3,5,6,7, and 10 in mice and IFITM1, 2, 3, 5, and 10 in humans (1, 2). The expression of several IFITM genes (e.g., those encoding IFITM1, 2, and 3) can be induced by type I, II, or III IFNs (3, 4). Although initial studies described possible roles of IFITM1, IFITM2, and IFITM3 in development, apoptosis, cell proliferation, and cell signaling (5-13), a subsequent report suggested that ectopic expression of IFITM1 in mouse L cells could restrict infection of vesicular stomatitis virus (VSV) (14). A decade later, gene silencing and ectopic expression studies established that IFITM proteins have antiviral activity in cell culture against members of the Flaviviridae, Orthomyxoviridae, Filoviridae, Rhabdoviridae, Retroviridae, Bunyaviridae, Reoviridae, Togaviridae,. Nonetheless, some enveloped and nonenveloped viruses appear to be resistant to the actions of IFITM proteins, including arenaviruses, papillomaviruses, cytomegaloviruses, and adenoviruses (16,17,29).IFITM proteins are transmembrane proteins. Although their precise membrane topology remains uncertain (5,6,15,(30)(31)(32)(33)(34)(35)(36), recent studies suggest that they are type II membrane proteins (35)(36)(37). Moreover, the cellular sublocalization of the IFITM proteins varies among family members, with IFITM1 expressed primarily at the plasma membrane, and IFITM2 and IFITM3 colocalizing predominantly with late endosomes (20,32). Based on the cellular localization and effects on specific steps in viral life cycles, IFITM1, IFITM2, and IFITM3 appear to restrict fusion and uncoating of viruses into the cytoplasm (33,38,39), with different IFITM proteins inhibiting specific viruses in distinct membrane compartments. Despite the intensive study of the IFITM proteins in cell culture, the precise mechanism of restriction of viral fusion has remained elusive. It has been suggested that IFITM proteins

Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication

“…The reasons for this discrepancy are not clear at present but may relate to altered gene expression kinetics of these two transcripts during naturally-acquired infection. In addition, previous studies have shown that IFITM1 is expressed on the plasma membrane and the early endosomes while IFITM3 can be preferentially detected in late endosomes(Bailey et al, 2014; Gorman et al, 2016; Monel et al, 2017; Savidis et al, 2016b). Nevertheless, there is evidence that ZIKV can antagonize interferon-signaling pathways by targeting key proteins involved in signaling downstream of the IFN receptor.…”

Identification of Residues Controlling Restriction versus Enhancing Activities of IFITM Proteins on Entry of Human Coronaviruses

“…Among the ISGs, those encoding IFN-induced transmembrane (IFITM) proteins, including IFITM1, IFITM2, and IFITM3, are widely expressed and can be induced by all three types of IFNs in many cell types. The IFITMs localize at the cell plasma membrane and endocytic vesicles and restrict the entry of enveloped RNA viruses from nine viral families (5), including some medically important human pathogens, such as influenza A virus (IAV), dengue virus (DENV), West Nile virus, Zika virus, chikungunya virus, Ebola virus (EBOV), Rift Valley fever virus, human immunodeficiency virus (HIV), and hepatitis C virus (3,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

Zika virus induces massive cytoplasmic vacuolization and paraptosis‐like death in infected cells

“…The mechanisms involved include altering the biophysical properties or cholesterol content of the cellular membranes in which they are found (Amini-Bavil-Olyaee et al, 2013;Li et al, 2013;Desai et al, 2014). These proteins inhibit many enveloped viruses, including influenza A virus (IAV), the flaviviruses WNV and DENV, severe acute respiratory syndrome coronavirus, hepatitis C virus, and Ebola virus (Brass et al, 2009;Zhu et al, 2015;Gorman et al, 2016) as well as HIV-1 and SIV (Lu et al, 2011). We and others identified new antiviral functions of IFITM proteins during HIV-1 infection: IFITM3 in the virus-producing cell is incorporated into nascent virions and decreases virus-cell fusion (Compton et al, 2014;Tartour et al, 2014;Yu et al, 2015).…”