IFITM genes, variants, and their roles in the control and pathogenesis of viral infections

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. Interferon-induced transmembrane proteins (IFITMs) are a family of small proteins that can be found in single cell organisms and are evolutionally conserved across vertebrates (Siegrist et al., 2011; Zhang et al., 2012). The human IFITM family comprises five members, including immune-related IFITM1, IFITM2, and IFITM3, as well as IFITM5 and IFITM10 with no known role in immunity. As key host defense genes, IFITMs evolved under the selective pressure of microorganism infection (Compton et al., 2016). IFITM proteins are involved in many aspects of virus-host interaction and play important roles in viral pathogenesis. 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). Mechanistically, these SNPs either alter the expression of IFITM3 or result in expression of N-terminally truncated IFITM3 isoform, Δ21-IFITM3, with reduced antiviral activity against different viruses (Everitt et al., 2012; Allen et al., 2017). In this review, we will summarize the findings on human IFITM structural features related with antiviral activity, and impact of genetic variation on IFITM antiviral function in the control and pathogenesis of viral infections in humans.