Human respiratory syncytial virus infection is inhibited by IFN-induced transmembrane proteins

Abstract

The IFN immune system plays an essential role in protecting the host against most viral infections. In order to explore the interactions between the IFN pathway and human respiratory syncytial virus (RSV) infection, and to identify potential IFN-stimulated genes (ISGs) that may be involved in suppressing the replication of RSV, we utilized an IFN pathway-specific microarray to study the effects of RSV infection on the IFN pathway in HeLa cells. We showed that RSV infection enhanced the expression of a series of ISGs, including oligoadenylate synthetase 2, IFITM1 (IFNinduced transmembrane protein 1) and myxovirus resistance 2. Our results also showed that the IFITM proteins potently inhibited RSV infection mainly by interfering with both virus entry and the subsequent replication steps, but not the attachment process. The antiviral effect of IFITM3 was not affected by ubiquitination modification. Furthermore, knocking down the endogenous and IFNinduced expression of IFITM1 and 3 facilitated RSV infection. Expression of the IFITM proteins was found to delay the phosphorylation of IFN regulatory factor 3 through interfering with the detection of viral RNA by MDA5 (melanoma differentiation-associated gene 5) and RIG-I (retinoic acid-inducible gene I). These results demonstrated that the restriction of RSV infection by the IFITM proteins was achieved through the inhibition of virus entry and replication, and they provided further insight for exploring the mechanism of IFITM-protein-mediated virus restriction.

The Interferon-Stimulated GeneIfitm3Restricts West Nile Virus Infection and Pathogenesis

“…Based primarily on studies in cell culture, the ISG IFITM3 has been suggested to have antiviral activity against a variety of viral pathogens, including flaviviruses (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). A demonstrable antiviral role for IFITM3/Ifitm3 in vivo has been established previously only for IAV and RSV (3,43,45,46).…”

“…Although initial studies described possible roles of IFITM1, IFITM2, and IFITM3 in development, apoptosis, cell proliferation, and cell signaling (5)(6)(7)(8)(9)(10)(11)(12)(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, and Paramyxoviridae families (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). 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).…”

Identification of Interferon-Stimulated Gene Proteins That Inhibit Human Parainfluenza Virus Type 3

“…With RSV, similar modest inhibition was found with IRF2, IRF7, MAP3K14, HPSE, and THBD, and surprisingly, with cGAS, a DNA sensor. Four ISG proteins, namely, viperin (82), OASL (85), IFITM1 and IFITM3 (86), specifically shown to inhibit RSV in directed studies, were not found to be inhibitory in the screen. The apparent differences could be due to a number of reasons, such as differences in cell lines, expression levels of the ISG proteins, viral load, and assay methods.…”

Accurate characterization of the IFITM locus using MiSeq and PacBio sequencing shows genetic variation in Galliformes

“…We attempted de novo assembly of Illumina MiSeq paired-end reads using three software packages (namely IVA, SGA and HGAP) resulting in only partial consensus sequence covering between 50 and 70% of the full chIFITM locus (including the flanking genes ATHL1 and B4GALNT4) (data not shown). The best assembly was generated using IVA, which produced the least number of contigs (13). In order to identify Illumina contigs that contained the BAC, and specifically the chIFITM locus, sequence similarity was used to compare the Illumina MiSeq contigs with the PacBio contig 2 (Additional file 4).…”

“…Interferon inducible transmembrane (IFITM) proteins are effectors of the immune system widely involved in restricting entry into cells of a broad range of viruses including Influenza viruses, Ebola and Zika [8][9][10][11][12][13][14]. In chickens, four IFITM genes have been annotated to date by the chicken gene nomenclature consortium (CGNC), namely chIFITM1 (LOC422993-3-like), chI-FITM3 (LOC770612-1-like), chIFITM5, and chIFITM10 [15][16][17][18][19][20][21][22].…”