Tuesday, December 15, 2015

Collapse of cholesterol biosythesis triggers universal anti-viral response

New study in journal Cell may provide mechanistic clue how obesity [and hyper-cholesterolemia] affect immunity. The authors showed that limiting cholesterol biosynthesis automatically triggers universal anti-viral defense state, mimicking natural response to viruses

Initially, the authors studied effect of type I IFNs [and its triggers] on lipid metabolism in macrophages. These pilot experiments reveal that de novo synthesis of cholesterol was inhibited by type I IFNs and its triggers, such as virus or PolyI:C. Interestingly, total cholesterol level or its import were not affected.

To decouple direct involvement of host defense response in lipid metabolism, the authors used LysM-Cre-Scap fl/fl mice that show limited lipid biosynthesis in myeloid cells. Indeed, Scap-/- macrophages displayed the same decrease in cholesterol synthesis as type I IFN treated control cells.  

Reduction of cholesterol synthesis in Scap-/- macrophages was accompanied with increased resistant to viral infection [similar resistance were observed in MKV (mevalonate kinase) and  HMG-CoA reductase deficient cells that have limitation in cholesterol biosynthesis].

This resistance in Scap-/- macrophages was transferable to control cells via soluble component in conditioned medium (type I IFNs).

Notably, the authors showed that anti-viral resistance in Scap-/- macrophages could be inhibited by exogenous free cholesterol.

Finally, the authors showed that DNA sensing STING-cGAS pathway was responsible for increased anti-viral state that accompanied collapse of cholesterol synthesis, and here too, free cholesterol supplementation was able to inhibit cGAS activity by its ligand [mechanism is unknown].

In summary, this study raises some of the important questions related to host metabolic shift observed during infections. Inhibition of anti-viral state by free cholesterol could explain diminished immune state observed in obese individuals. In addition, there are studies showing how cholesterol pathways, such as geranylgeranylation could influence TH17 and Foxp3+ Treg balance.

David Usharauli

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