Pyroptotic Macrophages Traps Against Shigella Infection

志贺氏杆菌是主要的肠道病原体，在世界范围内引起急性腹泻和细菌性痢疾，导致严重的死亡率和发病率。然而，目前还没有获得许可的疫苗来预防志贺氏菌病。志贺氏菌的毒力需要一个T3SS和至少30个分泌的效应物，这些效应物通常是功能冗余的，但却需要入侵宿主细胞、维持复制生态位、最小化警报信号和促进定植。我们之前的研究表明，通过Caspase-1炎症小体检测巨噬细胞中的flexneri T3SS活性，导致巨噬细胞焦亡。在最近的小鼠志贺氏菌病模型中，炎性体的作用仅集中在肠道上皮细胞（IECs）上。然而，一般认为志贺氏菌最初感染巨噬细胞，并利用热噬细胞死亡退出细胞，随后感染iec。另一方面，巨噬细胞热亡已知产生孔诱导陷阱（坑），捕获和中和细胞内细菌病原体。由于巨噬细胞焦亡被认为在志贺氏菌感染过程中起着双重作用，我们建议研究巨噬细胞炎症小体与福氏球菌之间的相互作用。我们提出了两个特定的目的：在Aim1中，我们将研究来自pit的热噬细胞如何捕获细胞内细菌。在目标2中。我们将定义热噬细胞和窝在体外和体内弗氏沙门氏菌感染中的作用。我们希望研究巨噬细胞热亡对福氏沙门氏菌感染的作用，将对更好地了解志贺氏菌感染期间的免疫和疾病病理具有重要意义，从而为开发更安全、更有效的新型疫苗提供基础。

Shigella spp. are major enteric pathogens, causing acute diarrhea and bacillary dysentery leading to severe mortality and morbidity worldwide. Yet, there is no licensed vaccine to prevent shigellosis. Shigella virulence requires a T3SS and at least 30 secreted effectors that are often functionally redundant, yet required to invade host cells, maintain a replicative niche, minimize alarm signals, and promote colonization. We previously showed that S. flexneri T3SS activity is detected in macrophages by Caspase-1 inflammasomes, resulting in pyroptosis. In the recent mouse shigellosis model, the role of the inflammasome is only focused on gut intestinal epithelial cells (IECs). However, it is generally believed that Shigella initially infect macrophages and takes advantage of pyroptotic cell death to exit the cells and subsequently infect IECs. On the other hand, macrophage pyroptosis is known to generate pore-induced traps (PITs), trapping, and neutralizing intracellular bacterial pathogens. Since macrophages pyroptosis is considered to play dichotomous roles during Shigella infection, we propose to investigate the interaction between macrophages' inflammasomes and S. flexneri. We propose two specific Aims: In Aim1, we will investigate how pyroptotic macrophages from PITs trap intracellular bacteria. In Aim 2. We will define the role of pyroptotic macrophages and PITs during S. flexneri infection in vitro and in vivo. We hope that examining the role of macrophages pyroptosis against S. flexneri infection, will be highly significant and relevant for better understanding immunity and disease pathologies during Shigella infection and thereby providing the basis for developing novel safer, and more effective vaccines.