Reprogramming lipid metabolism primes host antiviral immunity (INM7P.431)

Abstract

Abstract Oxysterols, or oxidized derivatives of cholesterol, have emerged as important regulators of adaptive and innate immunity. However, the molecular mechanisms by which these lipids facilitate host defense remain indeterminate. To better understand how cellular sterol metabolism influences innate immunity, we have generated gain- and loss-of-function macrophages that have key components of sterol homeostasis perturbed. Remarkably, we find that genetic manipulation of sterol biosynthetic capacity, and cellular sterol homeostasis, intrinsically alters its innate immune program. Genetic inhibition of the sterol biosynthetic pathway renders cells intrinsically resistant to pathogen challenge. Conversely, ectopically enforcing a sterol synthetic program renders cells more susceptible to viral infections. Mechanistic studies indicate that disruption of sterol synthesis in macrophages activates an array of host defense pathways, most notably a robust type 1 IFN response and upregulation of the anti-viral proteins MX-1 and MX-2. Current studies are focused on defining how inhibition of the sterol biosynthetic pathway engages anti-viral immunity and determining if this response is broadly applicable to other cell types. These studies provide proof -of-principle evidence that direct manipulation of sterol homeostatic state of a cell is intimately associated with host defense and suggests that metabolic manipulation converts a cell from a permissive to resistant viral immune state.