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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.

项目总结