小柯机器人

2022年3月16日，法国巴黎大学Marc Lecuit研究组在《自然》杂志发表论文，宣布他们发现细菌通过抑制fas介导的杀伤促进神经侵袭和持久性。

研究人员建立了一个临床相关神经李斯特菌（Lm）病的实验模型，用高毒性神经侵袭菌株感染人源化小鼠模型，研究表明细菌表面蛋白InlB以某种方式保护受感染的单核细胞免受Fas介导的CD8⁺ T细胞死亡，而这取决于c-Met、PI3激酶和FLIP。这种对特异性抗Lm细胞免疫杀伤的阻断延长了被感染单核细胞的寿命，从而有利于Lm通过感染单核细胞转移至大脑。由InlB介导细胞自主免疫抗性产生的细胞内生态位也促进了Lm脱落，这说明了为什么InlB是Lm的核心毒力基因。该研究揭示了一种特定的机制，通过该机制，细菌病原体通过使其对细胞介导的免疫产生抵抗力来延长其感染细胞的寿命。这促进了Lm在宿主体内的持久性、有利于其向中枢神经系统的传播。

据悉，中枢神经系统感染是最严重的感染之一，但对病原体进入大脑的机制仍知之甚少。模式微生物单核细胞增生Lm是一种主要的食源性病原体，可导致神经性李斯特菌病，这是中枢神经系统最致命的感染之一。尽管免疫抑制是公认的神经李斯特菌病导致宿主风险的因素，但对Lm产生神经侵袭的细菌因子知之甚少。

附：英文原文

Title: Bacterial inhibition of Fas-mediated killing promotes neuroinvasion and persistence

Author: Maudet, Claire, Kheloufi, Marouane, Levallois, Sylvain, Gaillard, Julien, Huang, Lei, Gaultier, Charlotte, Tsai, Yu-Huan, Disson, Olivier, Lecuit, Marc

Issue&Volume: 2022-03-16

Abstract: Infections of the central nervous system are among the most serious infections1,2, but the mechanisms by which pathogens access the brain remain poorly understood. The model microorganism Listeria monocytogenes (Lm) is a major foodborne pathogen that causes neurolisteriosis, one of the deadliest infections of the central nervous system3,4. Although immunosuppression is a well-established host risk factor for neurolisteriosis3,5, little is known about the bacterial factors that underlie the neuroinvasion of Lm. Here we develop a clinically relevant experimental model of neurolisteriosis, using hypervirulent neuroinvasive strains6 inoculated in a humanized mouse model of infection7, and we show that the bacterial surface protein InlB protects infected monocytes from Fas-mediated cell death by CD8+ T cells in a manner that depends on c-Met, PI3 kinase and FLIP. This blockade of specific anti-Lm cellular immune killing lengthens the lifespan of infected monocytes, and thereby favours the transfer of Lm from infected monocytes to the brain. The intracellular niche that is created by InlB-mediated cell-autonomous immune resistance also promotes Lm faecal shedding, which accounts for the selection of InlB as a core virulence gene of Lm. We have uncovered a specific mechanism by which a bacterial pathogen confers an increased lifespan to the cells it infects by rendering them resistant to cell-mediated immunity. This promotes the persistence of Lm within the host, its dissemination to the central nervous system and its transmission. Studies in a mouse model of neurolisteriosis show that the effector protein InlB produced by Listeria monocytogenes protects infected monocytes in the host from T cell-mediated cell death, and thereby increases bacterial neuroinvasion, persistence and transmission.

DOI: 10.1038/s41586-022-04505-7

Source: https://www.nature.com/articles/s41586-022-04505-7

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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