Egan Marisa S, O'Rourke Emily A, Mageswaran Shrawan Kumar, Zuo Biao, Martynyuk Inna, Demissie Tabitha, Hunter Emma N, Bass Antonia R, Chang Yi-Wei, Brodsky Igor E, Shin Sunny
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.
Elife. 2025 Mar 27;12:RP90107. doi: 10.7554/eLife.90107.
serovar Typhimurium is a facultative intracellular pathogen that utilizes its type III secretion systems (T3SSs) to inject virulence factors into host cells and colonize the host. In turn, a subset of cytosolic immune receptors respond to T3SS ligands by forming multimeric signaling complexes called inflammasomes, which activate caspases that induce interleukin-1 (IL-1) family cytokine release and an inflammatory form of cell death called pyroptosis. Human macrophages mount a multifaceted inflammasome response to infection that ultimately restricts intracellular bacterial replication. However, how inflammasomes restrict replication remains unknown. We find that caspase-1 is essential for mediating inflammasome responses to and restricting bacterial replication within human macrophages, with caspase-4 contributing as well. We also demonstrate that the downstream pore-forming protein gasdermin D (GSDMD) and Ninjurin-1 (NINJ1), a mediator of terminal cell lysis, play a role in controlling replication in human macrophages. Notably, in the absence of inflammasome responses, we observed hyperreplication of within the cytosol of infected cells as well as increased bacterial replication within vacuoles, suggesting that inflammasomes control replication primarily within the cytosol and also within vacuoles. These findings reveal that inflammatory caspases and pyroptotic factors mediate inflammasome responses that restrict the subcellular localization of intracellular replication within human macrophages.
鼠伤寒血清型沙门氏菌是一种兼性胞内病原体，它利用其三型分泌系统（T3SSs）将毒力因子注入宿主细胞并在宿主体内定殖。反过来，一部分胞质免疫受体通过形成称为炎性小体的多聚体信号复合物来响应T3SS配体，这些复合物激活半胱天冬酶，诱导白细胞介素-1（IL-1）家族细胞因子释放以及一种称为细胞焦亡的炎性细胞死亡形式。人类巨噬细胞对感染产生多方面的炎性小体反应，最终限制细胞内细菌复制。然而，炎性小体如何限制细菌复制仍不清楚。我们发现半胱天冬酶-1对于介导炎性小体对鼠伤寒血清型沙门氏菌的反应以及限制其在人类巨噬细胞内的复制至关重要，半胱天冬酶-4也有作用。我们还证明，下游成孔蛋白gasdermin D（GSDMD）和终末细胞裂解的介质Ninjurin-1（NINJ1）在控制鼠伤寒血清型沙门氏菌在人类巨噬细胞内的复制中发挥作用。值得注意的是，在没有炎性小体反应的情况下，我们观察到感染细胞胞质内鼠伤寒血清型沙门氏菌的超复制以及液泡内细菌复制增加，这表明炎性小体主要在胞质内以及液泡内控制鼠伤寒血清型沙门氏菌的复制。这些发现揭示，炎性半胱天冬酶和细胞焦亡因子介导炎性小体反应，从而限制人类巨噬细胞内细胞内鼠伤寒血清型沙门氏菌复制的亚细胞定位。
