Duke-National University of Singapore Medical School, Singapore.
Oxford University Clinical Research Unit (OUCRU), Ho Chi Minh City, Vietnam.
J Clin Invest. 2020 Oct 1;130(10):5223-5234. doi: 10.1172/JCI137536.
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.
登革病毒（DENV）感染需要胆固醇作为前病毒因子，尽管他汀类药物治疗在登革热患者中并未显示出抗病毒疗效。在这里，我们表明 DENV 感染可操纵在肝脏、脾脏和淋巴结等低氧微环境（缺氧）中居住的细胞中的胆固醇代谢。DENV 感染诱导了前蛋白转化酶枯草溶菌素/激肽释放酶 9（PCSK9）的表达，这降低了低密度脂蛋白受体（LDLR）的循环利用，从而减少了胆固醇摄取。我们发现，虽然 LDLR 的摄取会将胆固醇分布到各个细胞区室，但从头合成胆固醇会使这种脂质在内质网（ER）中富集。由于 ER 中胆固醇的富集，在 DENV 感染期间，内质网驻留的 STING 和 I 型 IFN（IFN）的激活受到抑制。我们在体外的发现得到了进一步支持，即在登革热患者中检测到高病毒血症和血浆渗漏严重程度增加时，血浆 PCSK9 水平升高。因此，我们的研究结果表明，PCSK9 在登革热发病机制中发挥了迄今为止尚未被认识到的作用，PCSK9 抑制剂可能是登革热患者的一种合适的宿主导向治疗方法。
