Regulation of host inflammatory responses and outcome in melioidosis by TLR5

描述（由申请方提供）：类鼻疽是一种常见的致死性新发传染病，由革兰氏阴性土壤腐殖酸和推定生物武器类鼻疽伯克霍尔德菌引起。流行于泰国东北部，死亡率超过40%。这种疾病是由于吸入或皮肤接种B而引起的。并最常表现为肺炎和败血症。肺炎使死亡几率增加两倍以上。类鼻疽是全球资源匮乏环境下肺炎和败血症巨大负担的代表，迫切需要新的治疗方法。我们已经确定了Toll样受体5（TLR 5），细胞表面鞭毛传感器，在类鼻疽的关键作用。TLR 5缺乏会加速小鼠呼吸道感染的死亡，但编码非功能性受体的TLR 5中常见的人类遗传变异与类鼻疽住院患者的生存率显着提高相关。该变体还与对B的较低促炎细胞因子应答相关。在离体血液刺激后，虽然唯一已知的TLR 5配体是鞭毛蛋白，但遗传变异携带者中降低的细胞因子应答与B无关。类鼻疽鞭毛蛋白，并且也在对B的应答中观察到。类鼻疽脂多糖，一种TLR 4激动剂。这些有趣的初步遗传数据需要进一步研究类鼻疽中TLR 5遗传变异和鞭毛蛋白-TLR 5轴的作用机制。对比小鼠和人类的表型强调了在人类中进行转化科学的重要性。我们推测，过度的主机炎症反应，这种嗜肺生物，调节TLR 5，但独立的鞭毛传感，有助于器官功能障碍和类鼻疽患者死亡。我们将利用PI的转化类鼻疽病研究计划和与泰国研究者的有力合作，以三种相互关联的方式来检验这一假设：1）确定TLR 5遗传变异是否与类鼻疽病患者的先天免疫激活减弱、炎症反应减少和临床结局改善相关，2）确定TLR 5如何调节对B的炎症反应。肺中的类鼻疽，和3）确定在B中是否存在由TLR 5遗传变体介导的差异信号传导。类鼻疽感染不依赖于鞭毛蛋白感应。更好地了解类鼻疽中的TLR 5将增加治疗干预的潜力，并对全球肺炎和败血症的其他病因产生影响。

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.