Cholesterol Metabolism and Innate Immunity

Recent evidence suggests a link between cholesterol metabolism and innate immunity. In a study published Tuesday in Immunity, researchers screened expression levels of multiple enzymes that regulate cholesterol metabolism to better understand how cholesterol metabolites combat infection. Their findings may aid in the development of new drugs to treat viral infections.

Upon viral infection, macrophages show reduced cholesterol synthesis accompanied by enhanced expression of antiviral genes, including the cytokine IFN-I. IFN-I can induce accumulation of the molecule 25-hydroxycholesterol (25-HC), which blocks viral entry. However, it has been unclear whether other cholesterol-associated metabolic products or enzymes regulate innate immunity.

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 two sources: human patients infected with hepatitis B virus and mice infected with vesicular stomatitis virus (VSV).

One of their findings was DHCR7, an enzyme that converts 7-DHC into cholesterol. Mutations in DHCR7 are known to cause mental retardation, but the role of DHCR7 in innate immunity has been unclear. This study shows that knocking out or inhibiting DHCR7 can promote IRF3 activation and IFNβ production to clear multiple viruses in vitro or in vivo.

DHCR7 can be inhibited by the chemotherapy drug Tamoxifen, which is normally used to treat breast cancer. Tamoxifen treatment also inhibits infection by VSV and the Zika virus at the cellular level, suggesting a possible application for Tamoxifen as an anti-infective. Additionally, 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.

Finally, the research shows that viral infection enhanced AKT3 expression, and 7-DHC treatment further activated AKT3. AKT3 and TBK1 both phosphorylate IRF3, resulting in IRF3 dimerization and full activation.