Salmonella protein AvrA promotes survival and dissemination within the host

沙门氏菌蛋白 AvrA 促进宿主内的存活和传播

基本信息

批准号：
7952725
负责人：
RHEINALLT MELFYN JONES
金额：
$ 7.75万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7952725
关键词：
Acute Address Adenoviruses Animal Model Apoptosis Apoptotic Bacteria Blood Circulation Bone Marrow Carrier State Cell Proliferation Cells Cessation of life Chronic Cultured Cells Data Diarrhea Disease Docking Drosophila genus Epithelial Feces Food Gastroenteritis Genetic Models Growth Health Immune Immune response Infection Ingestion Intestines Invaded Knowledge Lamina Propria Leukocytes Literature Longevity MAPK8 gene Mammalian Cell Mediating Modeling Molecular Mononuclear Mus Muscle Cramp NFKB Signaling Pathway Natural Immunity Neutrophil Infiltration Outcome Study Pathway interactions Patients Phagocytes Production Proliferating Proteins Public Health Research Role Salmonella Salmonella infections Salmonella typhimurium Signal Pathway Signal Transduction Staging System Therapeutic Intervention Transgenic Organisms United States Urine Vacuole cytokine enteric pathogen enteritis foodborne illness human disease macrophage pathogen public health relevance

项目摘要

DESCRIPTION (provided by applicant): Infectious Salmonella typhimurium serovars are a substantial health burden in the United States with an estimated 76 million cases of food borne illness and 5,000 associated deaths annually. Acute enteritis caused by Salmonella strains is manifested clinically by severe cramping and secretory diarrhea, and is the most common cause of infectious gastroenteritis in the United States. Certain Salmonella strains establish themselves within the host cells with no outward signs of disease because they have evolved sophisticated mechanisms to evade host innate immunity. Many infected patients become chronic pathogen carriers and continue to shed Salmonella in stools and urine for prolonged periods following initial invasion and acute gastroenteritis. These patients are a major public health concern because they are pathogen reservoirs. An extensive body of literature is devoted to identifying candidate molecules facilitating Salmonella survival, dissemination and persistence within the host. We have previously shown that some Salmonella strains secrete the preformed AvrA effector protein that potently inhibits the innate immune JNK and NF-kB signaling pathways, thus blocking cytokine production, neutrophil recruitment, and activation of apoptosis during the invasion stage of infection. However, the function of AvrA in mediating Salmonella dissemination and persistence within the host not been addressed, and will be the focus of this proposal. Intriguing preliminary data presented here demonstrate that concurrent AvrA expression and cytokine stimulation force proliferation of immune cells within the Drosophila animal model. We hypothesis that AvrA is responsible for skewing innate immune pathways, influencing Salmonella dissemination and/or chronic persistence. We propose to examine the mechanisms of AvrA mediated cell proliferation in 1) primary bone marrow derived leukocytes infected with nonreplicating adenovirus expressing AvrA, and 2) a murine salmonellosis infection model. In both aims, we will identify the proliferating leukocyte sub-sets using cell specific markers and FACS analysis. As an outcome of the study, we will advance current knowledge of bacterial strategies for survival during dissemination or in the chronic carrier state. PUBLIC HEALTH RELEVANCE: The research is significant because it will contribute to a full understanding of the evasion strategies evolved by enteric pathogens to escape the immune response and persist within the host. The positive impact of this study on advancing our knowledge of host/pathogen interactions will have relevance in human disease, allowing better understanding and potential treatment for chronic Salmonella infection.

描述（由申请人提供）：感染性沙门氏菌鼠伤寒沙门氏菌在美国是一个巨大的健康负担，估计每年有7600万例食物出生疾病和5,000例相关死亡。沙门氏菌菌株引起的急性肠炎在临床上通过严重的痉挛和分泌性腹泻表现出来，是美国传染性胃炎的最常见原因。某些沙门氏菌菌株在宿主细胞中没有疾病的迹象，因为它们已经发展出复杂的机制以逃避宿主先天免疫。许多受感染的患者成为慢性病原体携带者，并在初次入侵和急性胃肠炎后长时间继续在粪便和尿液中脱落沙门氏菌。这些患者是一个主要的公共卫生问题，因为它们是病原体库。广泛的文献专门用于识别候选分子，促进宿主内部的沙门氏菌存活，传播和持久性。我们先前已经表明，一些沙门氏菌菌株分泌预先形成的AVRA效应蛋白，该蛋白有效抑制先天免疫JNK和NF-KB信号传导途径，从而阻止细胞因子的产生，中性粒细胞募集和激活感染阶段的凋亡。但是，尚未解决AVRA在介导沙门氏菌传播和持久性中的功能，这将是该提议的重点。此处介绍的有趣的初步数据表明，果蝇模型中免疫细胞的同时表达和细胞因子刺激力增殖。我们假设AVRA负责歪曲先天免疫途径，从而影响沙门氏菌的传播和/或慢性持久性。我们建议检查1）原发性骨髓中衍生的白细胞感染了非复制腺病毒，表达AVRA的机制，以及2）一种鼠沙门氏菌感染模型。在这两个目标中，我们都将使用细胞特异性标记和FACS分析来鉴定白细胞子组的增殖。作为研究的结果，我们将促进当前对传播期间或慢性载体状态生存的细菌策略的了解。公共卫生相关性：这项研究很重要，因为它将有助于对肠道病原体进化的逃避策略的全面理解，以逃避免疫反应并在宿主内持续存在。这项研究对促进我们对宿主/病原体相互作用的了解的积极影响将与人类疾病相关，从而可以更好地理解和对慢性沙门氏菌感染的潜在治疗方法。