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.

项目摘要 由肠道肠孢子虫（STM）感染的巨噬细胞经历裂解炎症细胞 死亡称为凋亡，以消除沙门氏菌的复制生态位，并通过 释放IL-1细胞因子。尽管STM SPI-1活性触发了CASP1依赖性的快速凋亡，但仍可以 在没有CASP1的情况下，诱导caspase-8（CASP-8）依赖性细胞死亡。但是，在没有SPI-1-的情况下 介导的浸润和早期的凋亡，STM在巨噬细胞和 触发CASP1/11依赖性细胞死亡。有趣的是，我们的初步研究首次表明 与以前已研究的STM菌株对比，临床S. enterica血清分离株，包括S. 从宾夕法尼亚大学和DT104的兽医分离株获得的Enteritidis（SE）， 最近出现的STM菌株负责侵入性非细域沙门氏菌（INTS）疾病 撒哈拉非洲，触发casp1/11独立的细胞死亡，表明对临床的先天免疫应答 肠沙门氏菌与常用的实验室菌株诱导的肠道显着区别。 SE是领先 在美国的沙门氏菌病的原因，但我们目前缺乏有关它如何相互作用的机械知识 先天免疫系统。该提议的核心目标是定义宿主和沙门氏菌因素 负责晚期CASP1/11非依赖性死亡，这可能导致侵入性疾病的发病机理 由INT分离株引起。我们发现CASP8负责CASP1/11独立的细胞死亡触发 通过SE感染，该细胞死亡需要功能性SPI-2 T3S。一起，我们的研究引起了 假设沙门氏菌血清果酱具有触发casp8介导的独特病毒因子 在没有CASP1的情况下细胞死亡。我们将在该提案中以两个目标来检验该假设，以（1）定义 诱导casp8依赖性细胞死亡所需的宿主信号传导成分，（2） 机械地定义了诱导该SPI-2-和CASP8依赖性细胞所需的SE特异性细菌 死亡。定义此类因素将为病毒和宿主相互作用提供新的见解。 造成美国和欧洲大部分沙门氏菌感染的沙门氏菌血清射手。