Abstract
ABSTRACTTo transfer the viral genome into the host cell cytoplasm, internalized influenza A virus (IAV) particles depend on the fusion of the IAV envelope with host endosomal membranes. The antiviral host interferon (IFN) response includes the upregulation of interferon-induced transmembrane protein 3 (IFITM3), which inhibits the release of the viral content into the cytosol. Although IFITM3 induction occurs concomitantly with late endosomal/lysosomal (LE/L) cholesterol accumulation, the functional significance of this process is not well understood. Here we report that LE/L cholesterol accumulation itself plays a pivotal role in the early antiviral defense. We demonstrate that inducing LE/L cholesterol accumulation is antiviral in non-IFN-primed cells, restricting incoming IAV particles and impairing mixing of IAV/endosomal membrane lipids. Our results establish a protective function of LE/L cholesterol accumulation and suggest endosomal cholesterol balance as a possible antiviral target.
Highlights
To transfer the viral genome into the host cell cytoplasm, internalized influenza A virus (IAV) particles depend on the fusion of the IAV envelope with host endosomal membranes
We report that LE/L cholesterol accumulation already interferes with IAV infection at the early step of endosomal escape, contributing to the IFN-induced host cell defense against incoming IAV, and that the protective function is promoted via interferon-induced transmembrane protein 3 (IFITM3)
In line with previous reports, we show that antiviral IFN leads to IFITM3 upregulation and concomitant IFITM3-dependent LE/L cholesterol accumulation
Summary
To transfer the viral genome into the host cell cytoplasm, internalized influenza A virus (IAV) particles depend on the fusion of the IAV envelope with host endosomal membranes. We demonstrate that inducing LE/L cholesterol accumulation is antiviral in nonIFN-primed cells, restricting incoming IAV particles and impairing mixing of IAV/ endosomal membrane lipids. IMPORTANCE With annual epidemics occurring in all parts of the world and the risk of global outbreaks, influenza A virus (IAV) infections remain a major threat to public health. We report that accumulation of cholesterol in the LE/L compartment contributes to the IFN-induced host cell defense against incoming IAV. Our results establish cholesterol accumulation in LE/L per se as a novel antiviral barrier and suggest the endosomal cholesterol balance as a putative druggable host cell factor in IAV infection. The lower pH leads to a conformational change in HA, and subsequent hydrophobic interactions of HA with the endosomal membrane cause the formation of a fusion pore, allowing cytosolic entry and transport of the viral ribonucleoproteins to the nucleus [3, 4]
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