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.

志贺菌是主要的肠道病原体，引起急性腹泻和细菌性痢疾，导致世界范围内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。志贺氏菌毒力需要一个T3 SS和至少30个分泌的效应子，这些效应子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，最小化警报信号，并促进定植。我们以前表明，S。通过胱天蛋白酶-1炎性小体在巨噬细胞中检测到弗氏T3 SS活性，导致细胞凋亡。在最近的小鼠志贺菌病模型中，炎性小体的作用仅集中在肠上皮细胞（IEC）。然而，一般认为志贺氏菌最初感染巨噬细胞，并利用细胞的热变性死亡离开细胞，随后感染IEC。另一方面，已知巨噬细胞焦亡产生孔诱导陷阱（PIT），捕获和中和细胞内细菌病原体。由于巨噬细胞在志贺菌感染过程中起着双重作用，我们建议研究巨噬细胞炎性小体与志贺菌之间的相互作用。弗莱克斯内里。我们提出了两个具体的目标：在目标1中，我们将研究如何pyroptotic巨噬细胞从PIT陷阱细胞内细菌。在目标2中。我们将明确在S.在体外和体内的福氏杆菌感染。我们希望研究巨噬细胞的焦亡作用对S。福氏杆菌感染，将是非常重要的和相关的更好地了解免疫和疾病的病理过程中志贺氏菌感染，从而提供了基础，开发新的更安全，更有效的疫苗。