针对巨噬细胞中的胆固醇代谢，消除病毒感染

StephenW

Targeting cholesterol metabolism in macrophages to eliminate viral infection

Chinese Academy of Sciences Headquarters

Recent evidence suggests a link between cholesterol metabolism and innate immunity. Upon viral infection, macrophages show reduced cholesterol synthesis accompanied by enhanced expression of antiviral genes, including type I interferon (IFN-I).

IFN-I can induce 25-hydroxycholesterol (25-HC) accumulation, which blocks viral entry. However, it has been unclear whether other cholesterol-associated metabolic products or enzymes regulate innate immunity.

A new study published in Immunity now provides important new information. WANG Hongyan's team from the Center for Excellence in Molecular and Cellular Science, Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences (CAS), in collaboration with Prof. WEI Bin at Shanghai University (the former PI of the Wuhan Institute of Virology of CAS), screened expression levels of multiple enzymes that regulate cholesterol metabolism to better understand how cholesterol metabolites combats infection.

In order to find the enzymes or corresponding natural cholesterol metabolites involved in antiviral infection, the researchers screened differentially expressed genes in liver tissue from patients infected with hepatitis B virus and from mice infected with vesicular stomatitis virus (VSV).

DHCR7 (7-dehydrocholesterol reductase) is an enzyme that converts 7-dehydrocholesterol (7-DHC) into cholesterol. Patients carrying Dhcr7 mutations have mental retardation. However, the role of DHCR7 in innate immunity has been unclear. This study shows that DHCR7 knock-out (KO) or DHCR7 inhibitor treatment can promote IRF3 activation and type I interferon (IFNβ) production to clear multiple viruses in vitro or in vivo.

Interestingly, Tamoxifen, a chemotherapy drug used to treat breast cancer, was approved by the U.S. Food and Drug Administration to inhibit DHCR7's enzyme activity.

This study also reveals that Tamoxifen treatment inhibits infection by VSV and the Zika virus at the cellular level, suggesting a possible application for Tamoxifen as an anti-infective. Mice treated with the DHCR7 inhibitor AY9944 showed a significant increase in serum 7-DHC concentration, which promotes IRF3 phosphorylation and enhances IFNβ production in macrophages, thus protecting mice against lethal doses of VSV or the H1N1 influenza virus.

In addition, the research shows that viral infection enhanced AKT3 expression and 7-DHC treatment further activated AKT3. AKT3 directly bound and phosphorylated IRF3 at Ser385, together with TBK1-induced phosphorylation of IRF3 Ser386, to achieve IRF3 dimerization and full activation.

In conclusion, this study reveals that both the intermediate cholesterol metabolite 7-DHC and DHCR7 inhibitors promote IFN-I production and an antiviral response by activating AKT3 and IRF3. These findings may aid in the development of new drugs to treat viral infections. The research also provides new insights on how cholesterol metabolism regulates innate immunity.

StephenW

针对巨噬细胞中的胆固醇代谢，消除病毒感染

中国科学院总部

最近的证据表明胆固醇代谢和先天免疫之间存在联系。病毒感染后，巨噬细胞显示胆固醇合成减少，同时抗病毒基因（包括I型干扰素）的表达增强。

IFN-1可以诱导25-羟基胆固醇（25-HC）积累，从而阻止病毒进入。但是，尚不清楚其他胆固醇相关的代谢产物或酶是否调节先天免疫。

《免疫》杂志上发表的一项新研究现在提供了重要的新信息。来自中国科学院生物化学与细胞生物学研究所分子与细胞科学卓越中心的王鸿雁团队与上海大学魏斌教授（武汉病毒研究所原PI）合作（CAS）的研究，筛选了调节胆固醇代谢的多种酶的表达水平，以更好地了解胆固醇代谢物如何抵抗感染。

为了找到参与抗病毒感染的酶或相应的天然胆固醇代谢物，研究人员从感染了乙型肝炎病毒的患者和感染了水疱性口炎病毒（VSV）的小鼠中筛选了肝组织中差异表达的基因。

DHCR7（7-脱氢胆固醇还原酶）是一种将7-脱氢胆固醇（7-DHC）转化为胆固醇的酶。携带Dhcr7突变的患者患有智力障碍。但是，DHCR7在先天免疫中的作用尚不清楚。这项研究表明，DHCR7敲除（KO）或DHCR7抑制剂治疗可以促进IRF3激活和I型干扰素（IFNβ）的产生，以在体内或体外清除多种病毒。

有趣的是，用于治疗乳腺癌的化学疗法他莫昔芬被美国食品和药物管理局批准用于抑制DHCR7的酶活性。

这项研究还揭示了他莫昔芬治疗在细胞水平上抑制了VSV和寨卡病毒的感染，这表明他莫昔芬可能作为抗感染药应用。用DHCR7抑制剂AY9944处理的小鼠血清7-DHC浓度显着增加，从而促进IRF3磷酸化并增强巨噬细胞中IFNβ的产生，从而保护小鼠免受致命剂量的VSV或H1N1流感病毒的侵害。

此外，研究表明病毒感染增强了AKT3的表达，而7-DHC处理则进一步激活了AKT3。 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IRF3二聚化和完全激活。

总之，这项研究表明，中间胆固醇代谢产物7-DHC和DHCR7抑制剂均可通过激活AKT3和IRF3来促进IFN-1的产生和抗病毒反应。这些发现可能有助于开发治疗病毒感染的新药。该研究还提供了有关胆固醇代谢如何调节先天免疫力的新见解