IFITM3-containing exosome as a novel mediator for anti-viral response in dengue virus infection

Abstract

SummaryInterferon-inducible transmembrane proteins 1, 2 and 3 (IFITM1, IFITM2 and IFITM3) have recently been identified as potent antiviral effectors that function to suppress the entry of a broad range of enveloped viruses and modulate cellular tropism independent of viral receptor expression. However, the antiviral effect and mechanisms of IFITMs in response to viral infections remain incompletely understood and characterized. In this work, we focused our investigation on the function of the extracellular IFITM3 protein. In cell models of DENV-2 infection, we found that IFITM3 contributed to both the baseline and interferon-induced inhibition of DENV entry. Most importantly, our study for the first time demonstrated the presence of IFITM-containing exosome in the extracellular environment, and identified an ability of cellular exosome to intercellularly deliver IFITM3 and thus transmit its antiviral effect from infected to noninfected cells. Thus, our findings provide new insights in the basic mechanisms underlying the actions of IFITM3, which might lead to future development of exosome-mediated anti-viral strategies using IFITM3 as a therapeutic agent. Conceivably, variations in the basal and inducible levels of IFITMs, as well as in intracellular and extracellular levels of IFITMs, might predict the severity of dengue virus infections among individuals or across species.

Exosomal Interferon‐Induced Transmembrane Protein 2 Transmitted to Dendritic Cells Inhibits Interferon Alpha Pathway Activation and Blocks Anti–Hepatitis B Virus Efficacy of Exogenous Interferon Alpha

“…Increasing numbers of component proteins in exosomes were screened as biomarkers to assess the host immune microenvironment and improve personalized medicine . Sharing highly conserved transmembrane structure with IFITM2, IFITM1 and IFITM3 have been reported to be transferred between cells by exosomes . Our study proved that exosomes were critical vehicles for the transportation of IFITM2 protein (Fig.…”

The Interferon-Stimulated GeneIfitm3Restricts West Nile Virus Infection and Pathogenesis

“…Several studies have examined the interaction between IFITM proteins and Flaviviridae members in cell culture (15,19,23,(69)(70)(71). DENV, WNV, YFV, and recently ZIKV were shown to be susceptible to IFITM-mediated antiviral restriction, with IFITM3 being the most potent antiviral IFITM protein in cell culture (15,71,81).…”

“…Ifitm3 is an ISG that has been reported to restrict infection of several flaviviruses in cell culture, including WNV and DENV (15,19,(21)(22)(23)(69)(70)(71). To determine the role of Ifitm3 in restricting pathogenesis of a flavivirus in vivo, we inoculated 8-to 9-week-old WT and congenic Ifitm3 Ϫ/Ϫ C57BL/6 mice via a subcutaneous route with 10 2 FFU of a pathogenic strain of WNV (New York 1999).…”

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).…”