Dengue virus induces PCSK9 expression to alter antiviral responses and disease outcomes
Esther Shuyi Gan, … , Eng Eong Ooi, Sophie Yacoub
Esther Shuyi Gan, … , Eng Eong Ooi, Sophie Yacoub
Published July 9, 2020
Citation Information: J Clin Invest. 2020;130(10):5223-5234. https://doi.org/10.1172/JCI137536.
View: Text | PDF
Research Article Infectious disease

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.

Authors

Esther Shuyi Gan, Hwee Cheng Tan, Duyen Huynh Thi Le, Trieu Trung Huynh, Bridget Wills, Nabil G. Seidah, Eng Eong Ooi, Sophie Yacoub

×

Figure 3

PCSK9 augments DENV infection in primary myeloid cells.

Options: View larger image (or click on image) Download as PowerPoint
PCSK9 augments DENV infection in primary myeloid cells. (A) Plaque titer...
(A) Plaque titers for hypoxic primary monocytes 48 hpi with DENV infection. Cells were cultured without (black) or with supplementation of 400 ng/mL PCSK9 (purple) 24 hours before DENV2 infection. (B) Plaque titers for hypoxic primary MoDCs 48 hpi with DENV infection. Cells were cultured without (black) or with supplementation of 400 ng/mL PCSK9 (purple) 24 hours before DENV2 infection. (C) Volcano plot displaying 245 genes detected by NanoString in primary monocytes 24 hpi with DENV2. (D) Pathway analysis of genes that were most abundantly downregulated in PCSK9-supplemented primary monocytes as compared with nonsupplemented cells 24 hpi with DENV2 infection. Downregulated genes were analyzed against the GO biological pathway analysis and further summarized via REVIGO web server. (E) Plaque titers of hypoxic primary monocytes 48 hours after DENV2 infection. Cells were cultured without PCSK9 (black), with supplementation of 400 ng/mL PCSK9 (purple), or with PCSK9 and alirocumab (orange). (F) Plaque titers of hypoxic primary MoDCs 48 hours after DENV infection. Cells were cultured without PCSK9 (black), with supplementation of 400 ng/mL PCSK9 (purple), or with PCSK9 and alirocumab (orange). (G and H) mRNA expression of IFNB (D) and CXCL10 (E) in hypoxic MoDCs without (black) or with PCSK9 supplementation (purple) 6 hours after DENV2 infection. Experiments in A, B, E, and H were replicated 3 times, each with a minimum of 3 biological replicates. Representative data from 1 of these 3 independent experiments are shown. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by unpaired t test (A and B) and 1-way ANOVA corrected for multiple comparisons (E–H). Data in A, B, and E–H represent the mean ± SD.