Regulation of host inflammatory responses and outcome in melioidosis by TLR5

描述（由申请人提供）：类鼻疽病是由革兰氏阴性土壤腐生菌和假定的生物武器伪伯克霍尔德菌引起的一种通常致命的新兴传染病。在泰国东北部流行，死亡率超过40%。该疾病由吸入或皮肤接种假芽孢杆菌引起，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。类鼻疽病代表了资源匮乏地区全球巨大的肺炎和败血症负担，迫切需要新的治疗方法。我们已经确定了toll样受体5 (TLR5)，一种细胞表面鞭毛蛋白传感器，在类鼻疽中的关键作用。TLR5缺乏症会加速小鼠因呼吸道感染而死亡，但TLR5的一种常见人类基因变异编码一种无功能受体，与类鼻疽住院患者的生存率显著提高有关。该变异还与体外血液刺激下对假假芽孢杆菌的促炎性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，但该基因变异携带者的细胞因子反应降低与假假麦氏杆菌鞭毛蛋白无关，并且也观察到对假假麦氏杆菌脂多糖（TLR4激动剂）的反应。这些有趣的初步遗传数据需要进一步研究TLR5遗传变异和鞭毛蛋白-TLR5轴在类鼻疽中的作用机制。对比小鼠和人类表型强调了在人类中进行转化科学的重要性。我们假设宿主对这种嗜肺生物的过度炎症反应，由TLR5调节，但独立于鞭毛蛋白感知，导致类鼻疽患者的器官功能障碍和死亡。我们将利用PI的转化类瘤病研究项目以及与泰国研究人员的密切合作，以三种相互关联的方式验证这一假设：1)确定TLR5基因变异是否与类鼻疽患者先天免疫激活钝化、炎症反应减少、临床转诊结果改善有关；2)确定TLR5基因如何调节肺内假芽孢杆菌的炎症反应；3)确定假芽孢杆菌感染中TLR5基因变异介导的差异信号是否独立于鞭毛蛋白感知。更好地了解TLR5在类鼻疽中的作用将增加治疗干预的潜力，并对全球其他病因的肺炎和败血症产生影响。

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.