Interferon-mediated reprogramming of membrane cholesterol to evade bacterial toxins

Plasma membranes of animal cells are enriched for cholesterol. Cholesterol-dependent cytolysins (CDCs) are pore forming toxins secreted by bacteria that target membrane cholesterol for their effector function. Phagocytes are essential for clearance of CDC-producing bacteria; however, mechanisms these cells use to evade the deleterious effects of CDCs are largely unknown. Here, we report that interferon (IFN) signals convey resistance to CDC-induced pores on macrophages and neutrophils. We traced IFN-mediated resistance to CDCs to the rapid modulation of a specific pool of cholesterol in the plasma membrane of macrophages, without changing total cholesterol levels. Resistance to CDC pore formation requires production of the oxysterol 25-hydroxycholesterol, inhibition of cholesterol synthesis, and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking IFN’s ability to reprogram cholesterol metabolism abrogates cellular protection and renders mice more susceptible to CDC-induced tissue damage. These studies illuminate targeted regulation of membrane cholesterol content as a host-defense strategy.