SALMONELLA HIJACKING OF STAT3 AND CONSEQUENCES FOR DISEASE

沙门氏菌劫持 STAT3 及其疾病后果

基本信息

批准号：
9806916
负责人：
Dennis Chun-Yone Ko
金额：
$ 23.43万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-21 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9806916
关键词：
Acute Affect Animals Anti-inflammatory Antibiotics Autoimmune Diseases Autoimmune Process Bacteremia Binding Biochemical Biochemical Genetics Cell Line Cell Proliferation Cells Cessation of life Chronic Co-Immunoprecipitations Colitis Communicable Diseases Complex Conflict (Psychology)Cytokine Receptors DNA Data Development Disease Epidemiology Event Gastroenteritis Genes Genetic Polymorphism Genetic Transcription Genetic Variation Genotype Human Human Genetics IL6ST gene Immune Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Integration Host Factors Interleukin-10 Lead Malignant Neoplasms Mass Spectrum Analysis Mediating Molecular Morbidity - disease rate Multi-Drug Resistance Mus Mutate Pathologic Pathway interactions Phosphorylation Population Prophages Proteins Proteomics Regulation Regulatory Pathway Research Risk Role STAT3 gene Salmonella Salmonella infections Severities Severity of illness Signal Transduction Stat3 protein Systemic disease Testing Typhoid Fever Virulence base beta-Lactamase cell type cofactor comparative genomics cytokine genetic approach genome wide association study immune function immunoregulation in vivo member mortality novel novel therapeutic intervention receptor recruit transcription factor

项目摘要

Salmonellae cause an estimated 150 million cases of gastroenteritis and 25 million cases of invasive disease (enteric fever and non-typhoidal bacteremia), leading to 300,000 deaths per year. Salmonella manipulates multiple host cellular pathways through secreted effector proteins, but the molecular functions of most effectors, especially in animals and humans, remain poorly understood. A thorough characterization of how Salmonella effectors function and the pathways they target is required to understand how effectors impact infection and their long-term consequences on chronic inflammatory conditions, such as inflammatory bowel disease (IBD). IBD is an immune-mediated disease and whether IBD is affected by previous Salmonella infection is unclear, with conflicting evidence from both epidemiological and mouse studies. To understand how acute Salmonella infections may impact long-term immune modulation, studies are needed to determine how specific Salmonella effectors target host immune regulatory pathways, whether these changes persist beyond infection, and if these changes modulate risk or severity of disease. Through comparative genomics of Salmonella serovars, we recently identified a novel prophage-encoded Type III secreted effector: Salmonella anti-inflammatory response activator (SarA). SarA is the only Salmonella effector demonstrated to be necessary and sufficient to activate STAT3 (signal transducer and activator of transcription-3), a key transcription factor that regulates immune cell proliferation, development, and autoimmune conditions including IBD. SarA-mediated manipulation of STAT3 reprograms transcription in host cells and increases virulence in mice. We hypothesize SarA has both direct effects on cells injected with the effector and secondary consequences due to STAT3 target genes (such as the anti-inflammatory cytokine IL-10) that may cause persistent changes after infection has cleared. Therefore, the objective of this application is to determine how SarA activates STAT3 and affects immune cell populations during and after infection. Based on preliminary data, we hypothesize that SarA directly binds STAT3 and cofactors to assemble a STAT3- activating platform. Activation of this pathway phosphorylates STAT3 in multiple cell types, but it is unknown which cells are targeted in vivo and what the consequences of this activation are during and after infection. Therefore, we propose Specific Aims to 1) determine how SarA drives STAT3 activation through biochemical and genetic approaches and 2) determine the effects of SarA on immune cell populations and long-term consequences for the host, including severity of intestinal inflammation in colitis. Following completion of these aims, we will have determined how SarA mediates STAT3 signaling and how/if these signaling events alter immune function during and after infection. Revealing these mechanisms could lead to new therapeutic strategies for treating salmonellosis, as well as other STAT3-dependent pathological conditions including autoimmune diseases, cancer, and other infectious diseases.

沙门氏菌估计导致 1.5 亿例胃肠炎和 2500 万例侵袭性疾病（肠热病和非伤寒菌血症），每年导致 30 万人死亡。沙门氏菌操纵通过分泌效应蛋白的多种宿主细胞途径，但大多数效应蛋白的分子功能，尤其是在动物和人类中，人们仍然知之甚少。全面描述沙门氏菌如何要了解效应器如何影响感染及其作用，需要了解效应器的功能及其针对的途径。对炎症性肠病（IBD）等慢性炎症性疾病的长期影响。炎症性肠病是一种免疫介导的疾病，IBD 是否受到既往沙门氏菌感染的影响尚不清楚，流行病学和小鼠研究的证据相互矛盾。了解沙门氏菌的急性程度感染可能会影响长期的免疫调节，需要研究以确定沙门氏菌的具体作用效应器针对宿主免疫调节途径，这些变化是否在感染后持续存在，以及这些变化是否持续存在变化会调节疾病的风险或严重程度。通过沙门氏菌血清型的比较基因组学，我们最近鉴定了一种新的前噬菌体编码类型 III 分泌效应子：沙门氏菌抗炎反应激活剂（SarA）。 SarA 是唯一的沙门氏菌效应器被证明对于激活 STAT3（信号转导器和激活器）是必要且充分的 transcription-3)，调节免疫细胞增殖、发育和自身免疫的关键转录因子包括炎症性肠病 (IBD) 在内的病症。 SarA 介导的 STAT3 操作可重新编程宿主细胞中的转录增加小鼠的毒力。我们假设 SarA 对注射效应物的细胞有直接影响，并且 STAT3 靶基因（例如抗炎细胞因子 IL-10）引起的次要后果可能感染清除后引起持续变化。因此，该应用程序的目标是确定 SarA 如何激活 STAT3 并在感染期间和感染后影响免疫细胞群。根据初步数据，我们假设 SarA 直接结合 STAT3 和辅因子来组装 STAT3- 激活平台。该途径的激活会在多种细胞类型中磷酸化 STAT3，但目前尚不清楚哪些细胞在体内被靶向，以及感染期间和感染后这种激活的后果是什么。因此，我们提出具体目标 1) 确定 SarA 如何通过生化驱动 STAT3 激活和遗传方法，2) 确定 SarA 对免疫细胞群和长期的影响对宿主的后果，包括结肠炎中肠道炎症的严重程度。完成这些后目标，我们将确定 SarA 如何介导 STAT3 信号传导以及这些信号传导事件如何/是否改变感染期间和感染后的免疫功能。揭示这些机制可能会带来新的治疗方法治疗沙门氏菌病以及其他 STAT3 依赖性病理状况的策略，包括自身免疫性疾病、癌症和其他传染病。