Abstract
Interferon-induced transmembrane proteins (IFITMs) are a family of small proteins that localize in the plasma and endolysosomal membranes. IFITMs not only inhibit viral entry into host cells by interrupting the membrane fusion between viral envelope and cellular membranes, but also reduce the production of infectious virions or infectivity of progeny virions. Not surprisingly, some viruses can evade the restriction of IFITMs and even hijack the antiviral proteins to facilitate their infectious entry into host cells or promote the assembly of virions, presumably by modulating membrane fusion. Similar to many other host defense genes that evolve under the selective pressure of microorganism infection, IFITM genes evolved in an accelerated speed in vertebrates and many single-nucleotide polymorphisms (SNPs) have been identified in the human population, some of which have been associated with severity and prognosis of viral infection (e.g., influenza A virus). Here, we review the function and potential impact of genetic variation for IFITM restriction of viral infections. Continuing research efforts are required to decipher the molecular mechanism underlying the complicated interaction among IFITMs and viruses in an effort to determine their pathobiological roles in the context of viral infections in vivo.
Highlights
Specialty section: This article was submitted to Virology, a section of the journal Frontiers in Microbiology
Similar to many other host defense genes that evolve under the selective pressure of microorganism infection, Interferon-induced transmembrane proteins (IFITMs) genes evolved in an accelerated speed in vertebrates and many single-nucleotide polymorphisms (SNPs) have been identified in the human population, some of which have been associated with severity and prognosis of viral infection
Among the number of single-nucleotide polymorphisms (SNPs) in IFITM3 gene that have been identified in human populations, several are associated with disease severity and prognosis of influenza A virus (IAV) and other viral infections (Everitt et al, 2012; Zhang et al, 2015; Xu-Yang et al, 2016; Allen et al, 2017)
Summary
IFITMs have been shown to inhibit the infection of enveloped RNA viruses from 9 viral families (Perreira et al, 2013), non-enveloped RNA viruses, e.g., reovirus (Anafu et al, 2013) and foot-and-mouth disease virus (Xu et al, 2014), and several DNA viruses (Li et al, 2018). In vivo studies in IFITM3 knockout mice demonstrate the critical role of IFITM3 in restricting infection and reducing disease severity of infection by IAV (Bailey et al, 2012; Everitt et al, 2012), WNV (Gorman et al, 2016), Chikungunya virus and Venezuelan equine encephalitis virus (Poddar et al, 2016), and respiratory syncytial virus (Everitt et al, 2013). IFITM3 in mice protects lung epithelia cells from IAV infection, but it was shown to restricts IAV infection of lung dendritic cells, which traffic to lymph nodes to prime CD8+ T cell anti-viral response (Infusini et al, 2015). Lung resident memory CD8+ T cells in mice were programmed to retain IFITM3 expression, facilitating their survival and protection from viral infection during subsequent exposures (Wakim et al, 2013)
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