Defining mechanisms of Casp1/11-independent death triggered by clinical Salmonella Enteritidis

临床肠炎沙门氏菌触发的 Casp1/11 独立死亡的定义机制

• 批准号: 10452195
• 负责人: IGOR E BRODSKY
• 金额: $ 24.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452195
• 关键词: Affect; Affinity; Africa South of the Sahara; Alleles; Bioinformatics; CASP1 gene; CASP8 gene; Cell Death; Cells; Cessation of life; Clinical; Data; Disease; Disease Outbreaks; Europe; Family; Family member; Frequencies; Gastroenteritis; Goals; Host Defense; Immune response; Immune signaling; Immune system; Infection; Inflammatory; Inflammatory Response; Innate Immune Response; Innate Immune System; Interleukin-1; Interleukin-1 beta; Intestines; Knowledge; Laboratories; Leucine; Link; Lytic; MAPK8 gene; Mediating; Pathogenesis; Pathogenicity Island; Pathway interactions; Pennsylvania; Pharmacology; Phosphotransferases; Positioning Attribute; Process; RIPK1 gene; Salmonella; Salmonella Pathway; Salmonella enterica; Salmonella enteritidis; Salmonella infections; Salmonella typhimurium; Signal Transduction; Symptoms; Systemic infection; Testing; Time; Type III Secretion System Pathway; Typhoid Fever; United States; Universities; Variant; Veterinary Medicine; Veterinary Schools; Virulence; Virulence Factors; Yersinia; bacterial genetics; base; cytokine; foodborne illness; foodborne outbreak; genetic variant; in vivo; insight; macrophage; member; non-typhoidal Salmonella; novel; oral infection; prevent; public health relevance; response; stem

Project Summary Macrophages infected by Salmonella enterica serovar Typhimurium (STm) undergo a lytic inflammatory cell death known as pyroptosis to eliminate Salmonella’s replicative niche and promote inflammatory responses via release of IL-1 cytokines. While STm SPI-1 activity triggers a rapid Casp1-dependent pyroptosis, it can still induce Caspase-8 (Casp-8)-dependent cell death in the absence of Casp1. However, in the absence of SPI-1- mediated invasion and early pyroptosis, STm establishes a replicative compartment within macrophages and triggers a late Casp1/11-dependent cell death. Intriguingly, our preliminary studies show for the first time that in contrast to STm strains that have previously been studied, clinical S. enterica serovar isolates, including S. Enteritidis (SE), obtained from a strain bank of veterinary isolates at the University of Pennsylvania, and DT104, the recently-emerged STm strain responsible for invasive non-Typhoidal Salmonella (iNTS) disease in sub- Saharan Africa, trigger Casp1/11-independent cell death, suggesting that the innate immune response to clinical Salmonella enterica differs significantly from that induced by commonly used laboratory strains. SE is a leading cause of Salmonellosis in the United States, yet we currently lack mechanistic knowledge of how it interacts with the innate immune system. The central goal of this proposal is to define the host and Salmonella factors responsible for late Casp1/11-independent death, which may contribute to the pathogenesis of invasive disease caused by iNTS isolates. We find that Casp8 is responsible for the Casp1/11-independent cell death triggered by SE infection, and that this cell death requires a functional SPI-2 T3SS. Together, our studies provoke the hypothesis that Salmonella serovar Enteritidis possesses unique virulence factors that trigger Casp8-mediated cell death in the absence of Casp1. We will test this hypothesis in this proposal in two Aims that will (1) Define the host signaling components required to induce Casp8-dependent cell death in response to SE, and (2) Mechanistically define the SE-specific bacterial factors required to induce this SPI-2- and Casp8-dependent cell death. Defining such factors will provide new insight into the virulence and host interactions of less well-studied Salmonella serovars that are responsible for a large proportion of Salmonella infections in the US and Europe.

项目概要 被肠沙门氏菌鼠伤寒血清型 (STm) 感染的巨噬细胞经历裂解性炎症细胞 死亡称为焦亡，以消除沙门氏菌的复制生态位并通过以下方式促进炎症反应 IL-1细胞因子的释放。虽然 STm SPI-1 活性会触发快速的 Casp1 依赖性细胞焦亡，但它仍然可以 在 Casp1 缺失的情况下诱导 Caspase-8 (Casp-8) 依赖性细胞死亡。然而，在没有 SPI-1- STm 介导的侵袭和早期焦亡，在巨噬细胞内建立了复制区室， 触发晚期 Casp1/11 依赖性细胞死亡。有趣的是，我们的初步研究首次表明， 与之前研究过的 STm 菌株相反，临床分离出的肠沙门氏菌血清型，包括沙门氏菌。 肠炎球菌 (SE)，从宾夕法尼亚大学兽医分离株菌株库获得，以及 DT104， 最近出现的 STm 菌株导致亚种中的侵袭性非伤寒沙门氏菌 (iNTS) 疾病 撒哈拉非洲，触发 Casp1/11 独立的细胞死亡，表明先天免疫反应对临床 肠道沙门氏菌与常用实验室菌株诱导的沙门氏菌显着不同。 SE 是领先的 沙门氏菌病是美国沙门氏菌病的病因，但我们目前缺乏关于它如何与沙门氏菌相互作用的机制知识。 先天免疫系统。该提案的中心目标是确定宿主和沙门氏菌因素 导致晚期 Casp1/11 独立死亡，这可能有助于侵袭性疾病的发病机制 由 iNTS 分离株引起。我们发现 Casp8 负责触发 Casp1/11 独立的细胞死亡 SE 感染，并且这种细胞死亡需要功能性 SPI-2 T3SS。我们的研究共同激发了 假设肠炎沙门氏菌具有触发 Casp8 介导的独特毒力因子 Casp1 缺失时细胞死亡。我们将在本提案中的两个目标中测试这一假设，这两个目标将 (1) 定义 响应 SE 诱导 Casp8 依赖性细胞死亡所需的宿主信号成分，以及 (2) 从机制上定义诱导这种 SPI-2 和 Casp8 依赖性细胞所需的 SE 特异性细菌因子 死亡。定义这些因素将为研究较少的病毒的毒力和宿主相互作用提供新的见解 沙门氏菌血清型是造成美国和欧洲大部分沙门氏菌感染的原因。