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Dengue virus (DENV) infection requires cholesterol as a proviral factor, although statin treatment did not show antiviral efficacy in patients with dengue. Here, we show that DENV infection manipulated cholesterol metabolism in cells residing in low-oxygen microenvironments (hypoxia) such as in the liver, spleen, and lymph nodes. DENV infection induced expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), which reduces low-density lipoprotein receptor (LDLR) recycling and hence cholesterol uptake. We found that, whereas LDLR uptake would have distributed cholesterol throughout the various cell compartments, de novo cholesterol synthesis enriched this lipid in the endoplasmic reticulum (ER). With cholesterol enrichment in the ER, ER-resident STING and type I IFN (IFN) activation was repressed during DENV infection. Our in vitro findings were further supported by the detection of elevated plasma PCSK9 levels in patients with dengue with high viremia and increased severity of plasma leakage. Our findings therefore suggest that PCSK9 plays a hitherto unrecognized role in dengue pathogenesis and that PCSK9 inhibitors could be a suitable host-directed treatment for patients with dengue., Introduction Dengue is a major global health problem. Transmitted by the urban-adapted Aedes mosquitoes, an estimated 390 million individuals are infected with 1 of the 4 types of dengue virus [...]

Introduction: Dengue is a prevalent disease in tropical and subtropical countries with an estimated 400 million people infected annually. While significant advancement has been made in the chase for an effective dengue vaccine, the recently licensed Sanofi vaccine was, in contrast to in vitro data, only partially protective. Areas covered: This suggests that our understanding of the serological correlates for dengue is currently inadequate. With growing evidence supporting the role of fragment crystalizable gamma receptors (FcγRs) in antibody-mediated neutralization or antibody-dependent enhancement (ADE) of dengue virus (DENV) infection, FcγR-expressing cells have been increasingly used for measuring neutralizing antibody responses elicited by dengue vaccines. Here, we review the mechanisms of how FcγRs modulates both DENV neutralization and enhanced infections via its interactions with antibodies. Expert commentary: This review provides insights on the importance of factoring FcγRs for in vitro neutralization assays. Bridging the gap between in vitro and clinical observations would allow researchers to more accurately predict in vivo vaccine efficacy. [ABSTRACT FROM AUTHOR]