Abstract
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.
Highlights
Dengue is a major global health problem
Our findings show how cholesterol metabolism in cells that reside in organs with low-oxygen concentrations is altered upon dengue virus (DENV) infection to facilitate pathogenesis
Huh[7], BHK-21, and Vero cells were obtained from the American Type Culture Collection (ATCC) and cultured in DMEM (Gibco, Thermo Fisher Scientific) supplemented with 9% FCS (HyClone)
Summary
Transmitted by the urban-adapted Aedes mosquitoes, an estimated 390 million individuals are infected with 1 of the 4 types of dengue virus (DENV) annually (1). Infected individuals present with a range of clinical signs and symptoms, from asymptomatic infection, to self-limiting but debilitating acute febrile illness, to severe dengue characterized by hypovolemic shock from vascular leakage, organ dysfunction, and internal bleeding (2). A dengue vaccine, DENGVAXIA, has been licensed, it is only indicated for individuals who have had a prior DENV infection. DENGVAXIA, paradoxically, enhances DENV infection in those who are immunologically naive at vaccination and can only be given to individuals with evidence of prior DENV infection (5). No licensed antiviral drug is available to treat dengue. These limitations collectively hamper our ability to reduce the global burden of dengue
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