Pyroptotic Macrophages Traps Against Shigella Infection

焦亡巨噬细胞捕获志贺氏菌感染

• 批准号: 10646015
• 负责人: Youssef Aachoui
• 金额: $ 22.95万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-25 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646015
• 关键词: Actins; Acute Diarrhea; Age; Arginine; Arginine deiminase; Automobile Driving; Bacteria; CASP1 gene; Calcium; Cell Compartmentation; Cell Death; Cells; Chemotactic Factors; Child; Chromatin; Citrulline; Cytoskeleton; Cytosol; DNA Structure; Detection; Disease; Epithelial Cells; Epithelium; Hemorrhagic colitis; Histones; Immobilization; Immune; Immunity; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory Response; Interleukin-1 beta; Invaded; Licensing; Macrophage; Mediating; Membrane; Microtubules; Modeling; Morbidity - disease rate; Mus; Neutrophil Infiltration; Nuclear Envelope; Organelles; Pathogenesis; Pathology; Phagocytes; Pilot Projects; Play; Relaxation; Resistance; Role; Rupture; Shigella; Shigella Infections; Shigella flexneri; Side; Signal Transduction; Sterility; Structure; Swelling; Type III Secretion System Pathway; Vaccine Design; Vaccines; Vacuole; Virulence; antimicrobial; cell motility; content retention; cost; enteric pathogen; extracellular; gastrointestinal; gut colonization; improved; in vivo; intestinal epithelium; member; mortality; neutrophil; novel; pathogen; pathogenic bacteria; physiologic model; prevent; sensor

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.

志贺氏菌属是主要的肠道病原体，引起急性腹泻和细菌性痢疾，导致全世界严重的死亡和发病。然而，还没有获得许可的疫苗可以预防志贺氏菌病。志贺氏菌毒力需要 T3SS 和至少 30 个分泌效应器，这些效应器通常在功能上是冗余的，但需要侵入宿主细胞、维持复制生态位、最大限度地减少警报信号并促进定植。我们之前表明，Caspase-1 炎症小体在巨噬细胞中检测到弗氏链霉菌 T3SS 活性，从而导致细胞焦亡。在最近的小鼠志贺氏菌病模型中，炎症小体的作用仅集中在肠道上皮细胞（IEC）上。然而，人们普遍认为志贺氏菌最初感染巨噬细胞，并利用细胞焦亡退出细胞，随后感染 IEC。另一方面，已知巨噬细胞焦亡会产生孔诱导陷阱（PIT），捕获并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期间发挥二分作用，因此我们建议研究巨噬细胞炎症小体和福氏志贺氏菌之间的相互作用。我们提出了两个具体目标：在目标 1 中，我们将研究 PIT 中的焦亡巨噬细胞如何捕获细胞内细菌。在目标 2 中，我们将定义焦亡巨噬细胞和 PIT 在福氏链球菌体外和体内感染过程中的作用。我们希望，研究巨噬细胞焦亡对福氏志贺氏菌感染的作用，对于更好地了解志贺氏菌感染期间的免疫和疾病病理学具有非常重要的意义和相关性，从而为开发新型更安全、更有效的疫苗提供基础。