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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.

项目总结/摘要先天免疫系统利用种系编码的模式识别受体，调查细胞内外环境是否存在入侵微生物或危险发出信号，并采取适当的防御措施。炎性小体，多蛋白复合物响应微生物和内源性危险信号在胞质溶胶中组装，成为先天免疫监视系统的核心组成部分。一旦组装炎性小体蛋白水解激活半胱天冬酶-1，半胱天冬酶-1又诱导细胞死亡，产生IL-1β和IL-18。最近，非经典NLRP 3炎性体通路被LPS激活，LPS通过外膜囊泡进入胞质溶胶在感染革兰氏阴性菌如肠出血性大肠杆菌期间，大肠杆菌（EHEC）。胞质LPS结合并激活炎性半胱天冬酶，casino-11，然后介导细胞死亡、半胱天冬酶-1活化和下游IL-1细胞因子产生。炎性小体，包括半胱天冬酶-11介导的非典型炎性小体，在通过热原和IL-1应答清除感染因子。强大的选择压力这种来自宿主的感染促使病原体发展出主动对抗或逃避先天免疫反应然而，对caspase-11的调控知之甚少，细菌病原体介导的非典型炎性小体。该项目将解决这方面的知识差距，并将集中在检查非典型炎性小体的调制利用肠出血性大肠杆菌作为模式生物。在三个具体的研究中，该项目的目的将系统地描述两种细菌毒力因子如何抑制非典型炎性小体，并确定潜在的机制。识别致病菌沉默非典型炎性小体的机制是至关重要的，可能有助于设计针对革兰氏阴性菌感染的新治疗方法。

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 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

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

CD14在细胞内LPS传感中无关TLR4的关键作用。

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。