Immunity . . . Wang Hongyan/Wei Bin cooperation reveals a new mechanism for cholesterol metabolism regulation of congenital immune resistance to infection.

In the case of viral or bacterial infection, host cells can participate in anti infection through a variety of effective ways.among them, viral infection can induce host cells to change the expression of cholesterol metabolizing enzymes and metabolites, and cholesterol metabolism can also regulate the antiviral response of host cells.recent international frontier work indicates that targeting individual key cholesterol metabolic enzymes or corresponding metabolites can improve the function of antiviral infection.for example, knockout of cholesterol synthase SREBP2 can increase the expression of IFN β type 1 [1], or virus infection can induce the expression of cholesterol 25 hydroxylase (ch25h), resulting in the increase of 25-hydroxycholesterol (25-hc) and blocking virus invasion or replication [2-4].screening and identifying the anti infective function and mechanism of other cholesterol metabolic enzymes and natural metabolites is one of the research fields of innate immunity at home and abroad.on December 24, 2019, the research team of Wang Hongyan from the center for excellence and innovation of Molecular Cell Science (Institute of Biochemistry and cell biology, hereinafter referred to as the "molecular cell center") and Professor Wei Bin's Laboratory of Shanghai University (formerly Wuhan virus Institute of Chinese Academy of Sciences) published the research result: targeting 7-dehydrocholesterol Reductase integrates cholesterol metabolism and IRF3 activation to eliminate effect revealed that 7-dehydrocholesterol (7-DHC) and inhibitors targeting 7-dehydrocholesterol reductase DHCR7 can play an anti viral role.in order to find cholesterol metabolizing enzymes or corresponding natural products involved in antiviral infection, they screened liver tissues or macrophages from liver cancer patients infected with hepatitis B virus, mice infected with various types of viruses, and found that the expression of 7-dehydrocholesterol reductase (DHCR7) was significantly decreased in response to DNA virus or RNA virus infection.DHCR7 is a key enzyme that converts 7-dehydrocholesterol (7-DHC) into cholesterol. Patients with DHCR7 mutation show mental retardation [6], but it is not clear how DHCR7 regulates the function of innate immune antiviral infection.by constructing conditional DHCR7 knockout mice, DHCR7 knockout or knockout macrophages, and blocking DHCR7 enzyme activity with small molecule inhibitors, the IFN β production mediated by viral infection can be significantly enhanced. In addition, the content of 7-DHC was increased in liver tissues infected with virus, macrophages treated with DHCR7 deletion or its inhibitor, and the addition of natural product 7-DHC could also promote the anti infection function of macrophages.interestingly, tamoxifen has been approved by FDA to inhibit DHCR7 enzyme activity. This study found that tamoxifen can inhibit the infection of vesicular stomatitis virus (VSV) and zikv, suggesting the possibility of new use of old drugs.when mice were treated with AY9944, a DHCR7 inhibitor, the content of 7-DHC in serum was significantly increased, which protected mice against lethal dose of VSV and influenza virus (H1N1).this study revealed that both cholesterol intermediate 7-DHC and DHCR7 targeted inhibitors can play a role in anti viral infection, which will help to develop new strategies against new or severe viral infections.further exploration of the mechanism found that the macrophages at rest expressed a very low level of Akt3, virus infection promoted the expression of Akt3, and the metabolite 7-DHC could promote the activation of pi3k-akt3.in addition, Akt3, as a protein kinase, directly binds to IRF3, enhances the phosphorylation of IRF3 at serine 385, thus promoting the formation of IRF3 dimer and transferring to the nucleus, and finally enhancing the production of IFN β (figure below).Akt3 knockout mice significantly reduced the production of IFN β and increased the viral load, resulting in more death of mice.left: model diagram of the study; right: cartoon science picture: when an alien invades the earth, the early warning center (7-DHC) on the surface of the earth sends emergency signal (Akt3) to IRF3, which makes the earth guards (IFN β) assemble rapidly and transport them to the universe to resist alien bodies. In conclusion, 7-dehydrocholesterol reductase (DHCR7) in the cholesterol metabolism pathway can lead to the accumulation of 7-dehydrocholesterol, which can improve IFN β and antiviral function by activating Akt3 and IRF3.this study not only provides a new drug target to resist the infection of new or highly pathogenic viruses, but also provides a new insight into the regulation of innate immunity by reprogramming cholesterol metabolism. it is reported that Dr. Xiao Jun and Li Weiyun, postdoctoral doctors of Wang Hongyan laboratory, are the co first authors of this paper. The research has also been greatly assisted by Zhai Qiwei, Shanghai Institute of nutrition and health, Chinese Academy of Sciences, Chen Hualan, academician of Harbin Institute of veterinary medicine, Chinese Academy of Agricultural Sciences, and Yang Zhongzhou, Institute of model animals, Nanjing University. At the same time, references 1. 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