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Dengue virus induces PCSK9 expression to alter antiviral responses and disease outcomes.

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.

SUBMITTER: Gan ES

PROVIDER: S-EPMC7524462 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Dengue virus induces PCSK9 expression to alter antiviral responses and disease outcomes.

Gan Esther Shuyi ES Tan Hwee Cheng HC Le Duyen Huynh Thi DHT Huynh Trieu Trung TT Wills Bridget B Seidah Nabil G NG Seidah Nabil G NG Ooi Eng Eong EE Yacoub Sophie S

The Journal of clinical investigation 20201001 10

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 ch ...[more]

PMID: 32644974

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Dengue virus induces PCSK9 expression to alter antiviral responses and disease outcomes.

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Dengue virus induces PCSK9 expression to alter antiviral responses and disease outcomes.

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