Recent evidence suggests a link between cholesterol metabolism and innate immunity. After virus infection, macrophages showed decreased cholesterol synthesis and increased expression of antiviral genes including IFN-I. IFN-1 can induce the accumulation of 25 hydroxycholesterol, which will prevent the invasion of the virus. However, it is not clear whether other cholesterol related metabolites or enzymes regulate innate immunity.
In a new study, Wang Hongyan, a research group at the center for molecular cell science excellence and innovation, Institute of Biochemistry and cell biology, Chinese Academy of Sciences, and Wei bin, a professor at Shanghai University, worked together to screen the apparent levels of a variety of enzymes regulating cholesterol metabolism in order to better understand how cholesterol metabolites are resistant to viral infection. The related research results were recently published in the Journal of immunology. The title of the paper is "targeting 7-dehydrocholesterol reduction integrations cholesterol metabolism and IRF3 activation to achieve infection".
Immunity, 2019, doi:10.1016/j.immuni.2019.11.015
In order to find the enzymes involved in antiviral infection or the corresponding natural cholesterol metabolites, the researchers screened genes differentially expressed in liver tissue from patients infected with hepatitis B virus (HBV) and mice infected with vesicular stomatitis virus (VSV).
7-dehydrocholesterol reductase (DHCR7) is an enzyme that converts 7-dehydrocholesterol (7-DHC) to cholesterol. Patients with DHCR7 mutations have mental disorders. However, the role of DHCR7 in innate immunity is not clear. This new study shows that knockout of DHCR7 gene or DHCR7 inhibitor treatment can promote the activation of IRF3 and the production of interferon I (IFN β), so as to eliminate multiple viruses in vivo or in vitro.
Interestingly, tamoxifen, a chemotherapy drug used to treat breast cancer, has been approved by the US Food and Drug Administration (FDA) to inhibit the enzyme activity of DHCR7.
The new study also revealed that tamoxifen treatment inhibited VSV and Zika virus infection at the cellular level, suggesting that tamoxifen may be used as an anti-infective drug. The serum 7-DHC concentration of mice treated with AY9944, a DHCR7 inhibitor, increased significantly, which promoted the phosphorylation of IRF3 and the production of IFN β in macrophages, thus protecting mice from the lethal dose of VSV or H1N1 influenza virus.
In addition, the new study found that virus infection enhanced Akt3 expression, while 7-DHC treatment further activated Akt3. Akt3 binds IRF3 directly and induces IRF3 phosphorylation at ser385 site of IRF3. In addition, tbk1 induces IRF3 phosphorylation at ser386 site of IRF3, so as to realize the dimerization and full activation of IRF3.
All in all, this new study shows that the intermediate products of cholesterol metabolism, 7-DHC and DHCR7 inhibitors, can promote ifn-1 production and antiviral response by activating Akt3 and IRF3. These findings may contribute to the development of new drugs for the treatment of viral infection. The new study also offers new insights into how cholesterol metabolism regulates innate immunity.
1.Jun Xiao et al, Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection, Immunity (2019). DOI: 10.1016/j.immuni.2019.11.015.
2.Targeting cholesterol metabolism in macrophages to eliminate viral infection https://medicalxpress.com/news/2019-12-cholesterol-metabolism-macrophages-viral-infection.html