Abstract
Interferons (IFNs) establish dynamic host defense mechanisms by inducing various IFN-stimulated genes that encodes many antiviral innate immune effectors. IFN-inducible transmembrane (IFITM) proteins have been identified as intrinsic antiviral effectors, which block the entry of a broad spectrum of enveloped RNA viruses by interrupting virus-endosomal fusion. However, antiviral activity of IFITM proteins against mammalian DNA virus has not been demonstrated till date. Here, we sought to investigate the antiviral activities and mechanisms of interferon-inducible transmembrane protein 3 (IFITM3) protein against poxvirus infection. Analysis of expression kinetics of cell endogenous IFITM3 protein indicated that vaccinia virus (VACV) infection suppressed its translation, which was independent of IRF3 phosphorylation triggered by VACV. Although silencing of endogenous IFITM proteins did not affect their baseline antiviral effects in the cell, it has reduced the IFN-α-mediated inhibition of VACV infection, and also modulated VACV-induced cell death. Moreover, we discovered that overexpression of IFITM3 significantly restricted VACV infection, replication and proliferation mainly by interfering with virus entry processes prior to the virus nucleocapsid entry into the cytoplasm. Interestingly, IFITM3 overexpression showed an impact on virus binding. Furthermore, IFITM3 interfered with the cytosolic entry of virus through low pH-dependent fashion. Taken together, our findings provide the first evidence of exogenously expressed IFITM3 protein restricting infection of an enveloped DNA virus, thus expanding their antiviral spectrum. This study further explores the complex mechanism and provides novel insights into the interaction between virus infection and host defense.
Highlights
Interferon-stimulated genes (ISGs) are important integral components of host intrinsic immunity, which can be induced by interferons (IFN) or viral infection and exert antiviral activity at specific stages of the virus replication cycle [1]
To determine the role of endogenous interferon-inducible transmembrane protein 3 (IFITM3) in the interaction between the host cells and vaccinia virus, we first estimated the expression of IFITM3 in human cervical carcinoma cells (HeLa), A549, and 293T cells infected by vaccinia virus, respectively
We found that the expression of IFITM1 or IFITM3 in HeLa cells was further induced following IFNα2b treatment (Figure 1B) and subsequently IFNα2b markedly inhibited vaccinia virus (VACV) infection (Figure 1C)
Summary
Interferon-stimulated genes (ISGs) are important integral components of host intrinsic immunity, which can be induced by interferons (IFN) or viral infection and exert antiviral activity at specific stages of the virus replication cycle [1]. IFITM proteins (mainly referring to IFITM1, 2, and 3) have been reported to restrict the virus entry and infection of several pathogenic enveloped viruses, including influenza A virus (IAV) [8], West Nile virus (WNV) [4], dengue virus (DENV) [9], Ebola virus (EBOV) [10], SARS coronavirus [11], rift valley fever virus [12], Semliki forest virus [13], human immunodeficiency virus type-1 (HIV-1) [14, 15], respiratory syncytial virus (RSV) [16], and Zika virus [17]. Its antiviral mechanism is undefined, IFITM3 has been demonstrated to block virus entry by inhibiting the fusion of viral membrane with the endosomal membrane [24]
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