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

基本信息

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
项目类别：
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

项目摘要

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被称为细胞焦亡，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 活性会引发快速的 Casp1 依赖性焦亡，但它仍然可以在没有 Casp1 的情况下诱导 Caspase-8 (Casp-8) 依赖性细胞死亡。 STm 介导的侵袭和早期焦亡，在巨噬细胞内建立了一个复制区室，有趣的是，我们的初步研究首次表明，在与之前研究过的 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，它是一种主要的细菌。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。该提案的中心目标是定义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我们发现 Casp8 负责触发 Casp1/11 独立的细胞死亡。 SE 感染导致细胞死亡，并且这种细胞死亡需要功能性 SPI-2 T3SS。假设肠炎沙门氏菌具有触发 Casp8 介导的独特毒力因子在没有 Casp1 的情况下细胞死亡。我们将在本提案中通过两个目标来检验这一假设：(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。