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, the mechanisms by which these cells 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 changes to total cholesterol levels. Resistance to CDC-induced pore formation requires the production of the oxysterol 25-hydroxycholesterol (25HC), inhibition of cholesterol synthesis and redistribution of cholesterol to an esterified cholesterol pool. Accordingly, blocking the ability of IFN 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.

动物细胞的质膜富含胆固醇。胆固醇依赖性溶血素（CDCs）是细菌分泌的成孔毒素，这些细菌以膜胆固醇为靶标，发挥其效应功能。吞噬细胞对于清除产生CDC的细菌至关重要。但是，这些细胞逃避CDC有害作用的机制尚不清楚。在这里，我们报告干扰素（IFN）信号传达对巨噬细胞和中性粒细胞CDC诱导的毛孔的抵抗力。我们追踪到巨噬细胞质膜中特定的胆固醇池的快速调节而没有改变总胆固醇水平的IFN介导的对CDC的抗性。对CDC诱导的孔形成的抵抗力要求产生氧固醇25-羟基胆固醇（25HC），抑制胆固醇合成并将胆固醇重新分配至酯化胆固醇池。因此，阻断IFN重新编程胆固醇代谢的能力取消了细胞保护，并使小鼠更容易受到CDC诱导的组织损伤。这些研究阐明了靶向调节膜胆固醇的含量作为宿主防御策略。