Bacterial modulation of noncanonical inflammasome

非典型炎症小体的细菌调节

基本信息

批准号：
10311512
负责人：
Sivapriya Kailasan Vanaja
金额：
$ 39.88万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-16 至 2023-09-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311512
关键词：
Acute Address Affect Animal Model Anti-Bacterial Agents Antibiotics Autophagocytosis Bacteria Bacterial Infections Binding CASP1 gene Caspase Cell Death Cell Death Induction Child Citrobacter rodentium Cytosol Detection Development Endosomes Escherichia coli Escherichia coli EHEC Escherichia coli Infections Escherichia coli K12 Genes Genetic Engineering Genomic Islands Gram-Negative Bacteria Gram-Negative Bacterial Infections Hemolytic-Uremic Syndrome Hemorrhagic colitis Hospitalization Host Defense Human Immune Immune signaling Immunologic Surveillance Immunomodulators Infection Infectious Agent Inflammasome Inflammatory Innate Immune Response Innate Immune System Interleukin-1 Interleukin-1 beta Interleukin-18 Interleukin-6 Invaded Island Knowledge Libraries Life Lysosomes Mediating Membrane Mitomycin C Mobile Genetic Elements Multiprotein Complexes Mus Natural Immunity Nature Outcome Pathway interactions Pattern recognition receptor Persons Play Production Proteins Regulation Resistance Role Severity of illness Shiga Toxin Signal Pathway Signal Transduction Surveys System TNF gene Toxic effect Translations United States Vaccines Vesicle Virulence Virulence Factors antimicrobial arm base chemical genetics cytokine defense response design enteric pathogen genetic element in vivo inducible gene expression insight macrophage microbial mutant novel novel therapeutic intervention novel therapeutics pathogen pathogenic bacteria pressure response screening trafficking

项目摘要

Project Summary/Abstract The innate immune system employs germline-encoded pattern recognition receptors to survey the extra- and intra-cellular milieu for the presence of invading microbial or danger signals and mount appropriate defense responses. Inflammasomes, the multiprotein complexes assembled in the cytosol in response to microbial and endogenous danger signals, have emerged as a central component of the innate immune surveillance system. Once assembled inflammasomes proteolytically activate caspase-1, which in turn induces cell death and production of IL-1β and IL-18. Most recently a noncanonical NLRP3 inflammasome pathway was identified that is activated by LPS that enters the cytosol via outer membrane vesicles during infection with Gram-negative bacteria such as Enterohemorrhagic E. coli (EHEC). Cytosolic LPS binds and activates an inflammatory caspase, caspae-11, which then mediates cell death, caspase-1 activation and downstream IL-1 cytokine production. Inflammasomes, including the caspase-11-mediated noncanonical inflammasome, play a crucial role in the clearance of infectious agents via pyroptotic and IL-1 responses. A strong selection pressure from the host such as this drives pathogens to develop strategies to actively antagonize or evade innate immune responses. However, little is known about regulation of caspase-11- mediated noncanonical inflammasome by bacterial pathogens. This project will address this knowledge gap and will focus on examining the modulation of noncanonical inflammasome by bacteria utilizing EHEC as a model organism. The studies proposed in the three specific aims of this project will systematically characterize how two bacterial virulence factors inhibit the noncanonical inflammasome and determine the underlying mechanisms. Identifying the mechanisms by which pathogenic bacteria silence noncanonical inflammasome is crucial as it may aid in designing novel therapeutic approaches against Gram-negative infections.

项目摘要/摘要先天免疫系统采用种系编码的模式识别受体调查细胞内和细胞内环境是否存在入侵微生物或危险信号和适当的防御反应。炎症，多蛋白复合物响应微生物和内源性危险信号，在细胞质中组装，具有成为先天免疫监视系统的核心组成部分。一旦组装炎性酶体蛋白水解激活caspase-1，这又诱导细胞死亡和 IL-1β和IL-18的产生。最近是一种非规范的NLRP3炎性途径被鉴定出通过外膜蔬菜进入细胞质的LP激活的在革兰氏阴性菌感染期间，例如肠ha虫大肠杆菌（EHEC）。胞质LPS结合并激活炎症胱天蛋白酶CASPAE-11，然后介导细胞死亡，caspase-1激活和下游IL-1细胞因子产生。炎症，包括caspase-11介导的非法术炎性体，在通过凋亡和IL-1反应清除感染剂。强烈的选择压力从这样的主人那里驱动病原体来制定积极对抗或逃避先天免疫反应。但是，关于caspase-11-的调节知之甚少细菌病原体介导的非规范炎症体。这个项目将解决这些知识差距，并将重点研究非规范炎症体的调节通过使用EHEC作为模型生物的细菌。在三个特定中提出的研究该项目的目的将系统地表征两个细菌病毒因素如何抑制非规范炎症体并确定基本机制。识别致病细菌静音非规范炎症体的机制至关重要可能有助于设计针对革兰氏阴性感染的新型治疗方法。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inflammasome activation and evasion by bacterial pathogens.

DOI：
10.1016/j.coi.2020.11.006
发表时间：
2021-03
期刊：
Current opinion in immunology
影响因子：
7
作者：
Ta A;Vanaja SK
通讯作者：
Vanaja SK

Shiga toxin suppresses noncanonical inflammasome responses to cytosolic LPS.

DOI：
10.1126/sciimmunol.abc0217
发表时间：
2020-11-27
期刊：
Science immunology
影响因子：
24.8
作者：
Havira MS;Ta A;Kumari P;Wang C;Russo AJ;Ruan J;Rathinam VA;Vanaja SK
通讯作者：
Vanaja SK

A TLR4-independent critical role for CD14 in intracellular LPS sensing.

DOI：
10.1016/j.celrep.2022.110755
发表时间：
2022-05-03
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Vasudevan, Swathy O.;Russo, Ashley J.;Kumari, Puja;Vanaja, Sivapriya Kailasan;Rathinam, Vijay A.
通讯作者：
Rathinam, Vijay A.

Shigella "Osp"pression of innate immunity.

先天免疫的志贺氏菌“Osp”抑制。

DOI：
10.1016/j.cell.2022.05.027
发表时间：
2022
期刊：
Cell
影响因子：
64.5
作者：
Wright,SkylarS;Vanaja,SivapriyaKailasan
通讯作者：
Vanaja,SivapriyaKailasan

A bacterial autotransporter impairs innate immune responses by targeting the transcription factor TFE3.

DOI：
10.1038/s41467-023-37812-2
发表时间：
2023-04-11
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Ta, Atri;Ricci-Azevedo, Rafael;Vasudevan, Swathy O.;Wright, Skylar S.;Kumari, Puja;Havira, Morena S.;Surendran Nair, Meera;Rathinam, Vijay A.;Vanaja, Sivapriya Kailasan
通讯作者：
Vanaja, Sivapriya Kailasan