小柯机器人

美国加州大学Hiten D. Madhani研究团队发现分泌型真菌毒力效应因子通过 TLR4（Toll-like receptor 4） 触发过敏性炎症。这一研究成果发表在2022年7月27日出版的国际学术期刊《自然》上。

他们鉴定CPL1是由 C. neoformans 分泌的一种效应蛋白，可驱动巨噬细胞的替代激活（也称为 M2 极化），从而导致小鼠肺部感染。他们观察到 CPL1 增强的巨噬细胞极化需要 Toll 样受体 4，它是最有名的细菌内毒素受体，但也是过敏原诱导的 2 型反应的一种知之甚少的介质。他们表明这种效应是由 CPL1 本身引起的，而不是由污染脂多糖引起的。CPL1 对毒力至关重要，可驱动体内间质巨噬细胞的极化，并且需要 2 型细胞因子信号传导才能影响感染性。

值得注意的是，C. neoformans 在感染期间选择性地与极化的间质巨噬细胞相关联，这表明 C. neoformans 在宿主内产生自己的细胞内复制生态位的机制。这项工作确定了一个回路，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意外作用。

据介绍，侵入性真菌病原体是人类死亡和发病的主要原因。尽管已经在病原菌中鉴定出许多可重新编程先天免疫以促进毒力的分泌效应蛋白，但到目前为止，还没有人类真菌病原体产生的类似分泌效应蛋白的例子。新型隐球菌是真菌性脑膜炎的最常见原因，也是 AIDS 的主要病原体，可诱导以肺嗜酸性粒细胞增多和交替活化的巨噬细胞为特征的 2 型致病性反应。

附：英文原文

Title: Secreted fungal virulence effector triggers allergic inflammation via TLR4

Author: Dang, Eric V., Lei, Susan, Radkov, Atanas, Volk, Regan F., Zaro, Balyn W., Madhani, Hiten D.

Issue&Volume: 2022-07-27

Abstract: Invasive fungal pathogens are major causes of human mortality and morbidity1,2. 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 macrophages3,4,5,6,7,8. 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 responses9,10,11,12. 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.

DOI: 10.1038/s41586-022-05005-4

Source: https://www.nature.com/articles/s41586-022-05005-4

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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