Regulation of host inflammatory responses and outcome in melioidosis by TLR5

TLR5 对类鼻疽中宿主炎症反应和结果的调节

• 批准号: 8469901
• 负责人: Timothy Eoin West
• 金额: $ 57.36万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469901
• 关键词: Agonist; Alleles; Alveolar Macrophages; Animals; Biological; Blood; Breathing; Burkholderia pseudomallei; Candidate Disease Gene; Case Fatality Rates; Cell surface; Cells; Cessation of life; Clinical; Collaborations; Cutaneous; Data; Disease; Emerging Communicable Diseases; Employee Strikes; Epithelial Cells; Etiology; Flagellin; Functional disorder; Genes; Genetic; Genetic Polymorphism; Genome; Genotype; Homozygote; Human; Human Genetics; Immune response; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; International; Ligands; Lipopolysaccharides; Lung; Mastigophora; Mediating; Melioidosis; Microarray Analysis; Mus; Organ; Organ failure; Organism; Other Genetics; Outcome; Pathway interactions; Patients; Phenotype; Plasma; Pneumonia; Prospective Studies; Public Health; Regulation; Research; Research Personnel; Resources; Respiratory Tract Infections; Role; Rural; Sepsis; Signal Transduction; Soil; TLR4 gene; Testing; Thailand; Therapeutic Intervention; Time; Toll-Like Receptor 5; Transgenic Mice; Translational Research; Variant; Work; burden of illness; cohort; cytokine; genetic variant; immune activation; improved; monocyte; mortality; neutrophil; novel; programs; receptor; response; sensor; therapy development

DESCRIPTION (provided by applicant): Melioidosis is an often lethal emerging infectious disease caused by the Gram-negative soil saprophyte and putative bioweapon, Burkholderia pseudomallei. Endemic in northeast Thailand, mortality exceeds 40%. The disease results from inhalation or cutaneous inoculation with B. pseudomallei and most frequently presents with pneumonia and sepsis. Pneumonia confers over a two-fold increase in the odds of death. Melioidosis is representative of the huge global burden of pneumonia and sepsis in low resource settings, for which new therapies are urgently needed. We have identified a key role for Toll-like receptor 5 (TLR5), a cell surface flagellin sensor, in melioidosis. TLR5-deficiency accelerates death from respiratory infection in mice but a common human genetic variant in TLR5 that encodes a non-functional receptor is associated with dramatically improved survival in hospitalized patients with melioidosis. The variant is also associated with lower pro- inflammatory cytokine responses to B. pseudomallei upon stimulation of blood ex vivo. Although the only known ligand of TLR5 is flagellin, the reduced cytokine responses in carriers of the genetic variant are independent of B. pseudomallei flagellin and are also observed in response to B. pseudomallei lipopolysaccharide, a TLR4 agonist. These intriguing preliminary genetic data necessitate additional study of the mechanisms underlying the effect of the TLR5 genetic variant and the flagellin-TLR5 axis in melioidosis. The contrasting murine and human phenotypes emphasize the importance of performing translational science in humans. We hypothesize that an excessive host inflammatory response to this lung-tropic organism, regulated by TLR5 but independent of flagellin sensing, contributes to organ dysfunction and death in melioidosis patients. We will leverage the PI's translational melioidosis research program and robust collaboration with Thai investigators to test this hypothesis in three inter-related ways: 1) Determine whether the TLR5 genetic variant is associated with blunted innate immune activation, reduced inflammatory responses, and improved clinical outcome in melioidosis patients, 2) determine how TLR5 regulates inflammatory responses to B. pseudomallei in the lung, and 3) determine whether differential signaling mediated by the TLR5 genetic variant in B. pseudomallei infection is independent of flagellin sensing. A better understanding of TLR5 in melioidosis will increase the potential for therapeutic interventions and have ramifications for other etiologies of pneumonia and sepsis worldwide.

描述(申请人提供)：类鼻疽病是一种通常致命的新出现的传染病，由革兰氏阴性土壤腐生真菌和可能的生物武器，假鼻疽伯克霍尔德氏菌引起。在泰国东北部流行，死亡率超过40%。这种疾病是由吸入或皮肤接种假腮腺炎引起的，最常见的症状是肺炎和败血症。肺炎使死亡几率增加两倍以上。类鼻疽是肺炎和败血症在低资源环境下造成的巨大全球负担的代表，为此迫切需要新的治疗方法。我们已经确定了Toll样受体5(TLR5)在类鼻疽病中的关键作用，TLR5是细胞表面鞭毛蛋白传感器。TLR5缺乏会加速小鼠因呼吸道感染而死亡，但TLR5中一种常见的人类基因变异编码一个不起作用的受体，与显着提高住院的类鼻疽患者的存活率有关。该变异还与体外刺激血液时对假腮腺炎杆菌的促炎细胞因子反应降低有关。虽然TLR5唯一已知的配体是鞭毛蛋白，但该基因变体携带者细胞因子反应的降低不依赖于假单胞菌鞭毛蛋白，也可以观察到对TLR4激动剂假单胞菌脂多糖的反应。这些耐人寻味的初步遗传数据需要进一步研究TLR5基因变异和鞭毛蛋白-TLR5轴在类鼻疽病中的作用机制。小鼠和人类的不同表型强调了在人类身上进行翻译科学的重要性。我们推测，宿主对这种嗜肺微生物的过度炎症反应，受TLR5调节，但不依赖鞭毛感觉，导致类鼻疽病患者的器官功能障碍和死亡。我们将利用PI的翻译类鼻疽病研究计划以及与泰国研究人员的密切合作，通过三种相互关联的方式来检验这一假说：1)确定TLR5基因变体是否与类鼻疽病患者的先天性免疫激活钝化、炎症反应减少和临床预后改善有关；2)确定TLR5如何调节肺部对假鼻疽杆菌的炎症反应；以及3)确定假鼻疽杆菌感染中TLR5基因变体介导的差异信号是否独立于鞭毛感知。更好地了解TLR5在类鼻疽病中的作用将增加治疗干预的可能性，并对世界范围内肺炎和败血症的其他病因产生影响。