Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
Nature. 2022 Aug;608(7921):161-167. doi: 10.1038/s41586-022-05005-4. Epub 2022 Jul 27.
Invasive fungal pathogens are major causes of human mortality and morbidity. Although numerous secreted effector proteins that reprogram innate immunity to promote virulence have been identified in pathogenic bacteria, so far, there are no examples of analogous secreted effector proteins produced by human fungal pathogens. Cryptococcus neoformans, the most common cause of fungal meningitis and a major pathogen in AIDS, induces a pathogenic type 2 response characterized by pulmonary eosinophilia and alternatively activated macrophages. Here, we identify CPL1 as an effector protein secreted by C. neoformans that drives alternative activation (also known as M2 polarization) of macrophages to enable pulmonary infection in mice. We observed that CPL1-enhanced macrophage polarization requires Toll-like receptor 4, which is best known as a receptor for bacterial endotoxin but is also a poorly understood mediator of allergen-induced type 2 responses. We show that this effect is caused by CPL1 itself and not by contaminating lipopolysaccharide. CPL1 is essential for virulence, drives polarization of interstitial macrophages in vivo, and requires type 2 cytokine signalling for its effect on infectivity. Notably, C. neoformans associates selectively with polarized interstitial macrophages during infection, suggesting a mechanism by which C. neoformans generates its own intracellular replication niche within the host. This work identifies a circuit whereby a secreted effector protein produced by a human fungal pathogen reprograms innate immunity, revealing an unexpected role for Toll-like receptor 4 in promoting the pathogenesis of infectious disease.
侵袭性真菌病原体是人类死亡和发病的主要原因。虽然已经在致病性细菌中鉴定出了许多能够重新编程先天免疫以促进毒力的分泌效应蛋白，但迄今为止，还没有人类真菌病原体产生类似分泌效应蛋白的例子。新生隐球菌是最常见的真菌性脑膜炎病原体，也是艾滋病的主要病原体，它诱导一种致病的 2 型反应，其特征是肺部嗜酸性粒细胞增多和交替激活的巨噬细胞。在这里，我们鉴定出 CPL1 是新生隐球菌分泌的一种效应蛋白，它驱动巨噬细胞的交替激活（也称为 M2 极化），从而使小鼠肺部感染。我们观察到，CPL1 增强的巨噬细胞极化需要 Toll 样受体 4，该受体最著名的是细菌内毒素的受体，但也是过敏原诱导的 2 型反应的一个了解甚少的介质。我们表明，这种效应是由 CPL1 本身引起的，而不是由污染的脂多糖引起的。CPL1 对毒力是必需的，它在体内驱动间质巨噬细胞的极化，并需要 2 型细胞因子信号传导来发挥其对感染性的影响。值得注意的是，新生隐球菌在感染过程中与极化的间质巨噬细胞选择性地相关，这表明了新生隐球菌在宿主内产生自身细胞内复制龛的一种机制。这项工作确定了一种电路，即由人类真菌病原体产生的分泌效应蛋白重新编程先天免疫，揭示了 Toll 样受体 4 在促进传染病发病机制中的一个意外作用。
