2019年12月24日，《免疫》在线发表了中国科学院分子细胞科学卓越创新中心（上海生物化学与细胞生物学研究所）王红艳研究员团队与上海大学魏滨教授（原中科院武汉病毒所研究员）实验室合作的研究成果。他们发现靶向7-脱氢胆固醇还原酶能够联合胆固醇代谢和IRF3激活，从而消除感染。

研究人员发现，在DNA和RNA病毒感染后，巨噬细胞会降低7-脱氢胆固醇还原酶（DHCR7）的表达。DHCR7缺乏或用天然产物7-脱氢胆固醇（7-DHC）处理可以特异性地促进IRF3（而不是TBK1）的磷酸化并增强巨噬细胞中I型干扰素（IFN-I）的产生。研究人员进一步阐明，病毒感染或7-DHC处理可增强AKT3的表达和激活。AKT3在Ser385处直接结合IRF3并使其磷酸化，以及TBK1诱导的IRF3 Ser386磷酸化，从而实现IRF3二聚化。DHCR7的删除和DHCR7抑制剂（包括AY9944和化疗药物他莫昔芬）可促进Zika病毒和多种病毒在体外或体内的清除。总之，研究人员认为DHCR7抑制剂和7-DHC是靶向新兴或高致病性病毒的潜在疗法。

据了解，最期的研究工作表明胆固醇代谢会影响抵抗感染的先天免疫反应。但是，关键的酶或涉及的天然产物和机理尚未得到很好的阐明。

附：英文原文

Title: Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection

Author: Jun Xiao, Weiyun Li, Xin Zheng, Linlin Qi, Hui Wang, Chi Zhang, Xiaopeng Wan, Yuxiao Zheng, Ruiyue Zhong, Xin Zhou, Yao Lu, Zhiqi Li, Ying Qiu, Chang Liu, Fang Zhang, Yanbo Zhang, Xiaoyan Xu, Zhongzhou Yang, Hualan Chen, Qiwei Zhai, Bin Wei, Hongyan Wang

Issue&Volume: December 24, 2019

Abstract: Recent work suggests that cholesterol metabolism impacts innate immune responses againstinfection. However, the key enzymes or the natural products and mechanisms involvedare not well elucidated. Here, we have shown that upon DNA and RNA viral infection,macrophages reduced 7-dehydrocholesterol reductase (DHCR7) expression. DHCR7 deficiencyor treatment with the natural product 7-dehydrocholesterol (7-DHC) could specificallypromote phosphorylation of IRF3 (not TBK1) and enhance type I interferon (IFN-I) productionin macrophages. We further elucidated that viral infection or 7-DHC treatment enhancedAKT3 expression and activation. AKT3 directly bound and phosphorylated IRF3 at Ser385,together with TBK1-induced phosphorylation of IRF3 Ser386, to achieve IRF3 dimerization.Deletion of DHCR7 and the DHCR7 inhibitors including AY9944 and the chemotherapy drugtamoxifen promoted clearance of Zika virus and multiple viruses in vitro or in vivo. Taken together, we propose that the DHCR7 inhibitors and 7-DHC are potential therapeuticsagainst emerging or highly pathogenic viruses.

DOI: 10.1016/j.immuni.2019.11.015

Source: https://www.cell.com/immunity/fulltext/S1074-7613(19)30496-0