Determinants of Outcome and Recurrent Infections in Melioidosis

 描述(申请人提供)：类鼻疽病是一种热带传染病，由吸入、摄入或接种革兰氏阴性土壤腐生菌和一级选择剂假鼻疽伯克霍尔德菌引起。尽管在整个热带地区越来越多地认识到类鼻疽病，但它在泰国东北部高度流行，在那里它被并列为第二大主要传染病死亡原因。即使接受了适当的抗生素治疗，40%的患者也会死亡，其中许多人死于严重的脓毒症。在幸存者中，约10%复发，大多数在第一年。至于败血症的其他原因，目前还没有成功的免疫调节治疗方法。因此，类鼻疽病是泰国的一个重大公共卫生威胁，迫切需要新的治疗方法。近八年来，我们已经成功地实施了泰美合作，以阐明人类类鼻疽的宿主防御机制。我们对菌血症患者的整个外显子组测序研究已经确定了可能决定类鼻疽病预后的候选基因和炎症途径。我们这项提议的合作者Chaussabel博士和Lertmongkolchai博士分析了血液转录组，以创建将类鼻疽病与其他败血症原因区分开来的特征，并确定类鼻疽病特有的生物途径激活。虽然人类在类鼻疽病中的炎症反应仍然知之甚少，但我们的初步结果突出了先进技术应用于类鼻疽病的前景。我们建议建立类鼻疽病ICIDR，通过应用最先进的技术来全面阐明类鼻疽病发病机制和治疗反应差的免疫学和炎症机制，从而加强现有的国际科学关系。我们将通过完整的转录组RNA测序和高通量单细胞多色流式细胞术来加强我们的整个外显子组测序分析，用于复杂的类鼻疽患者的免疫表型。该提案围绕一项针对类鼻疽病的前瞻性、多中心纵向队列研究而设计，包括详细的临床和生物表型分析，以及专家支持的对所有结果数据的国内分析，该提案将直接增强泰国 类鼻疽研究能力。我们的目标是：1)确定急性类鼻疽病的宿主炎症变化，以阐明发病机制并预测死亡；2)确定允许复发的免疫学机制；3)验证新发现的影响类鼻疽病生存的遗传决定因素。除了本申请中涉及的科学目标外，该提案还建立了一个独特和持久的类鼻疽研究平台，总部设在临床类鼻疽研究的最佳地点，具有巨大的潜力影响泰国人和全球公民的公共健康。

 DESCRIPTION (provided by applicant): Melioidosis is a tropical infection caused by inhalation, ingestion, or inoculation of the Gram-negative soil saprophyte and Tier 1 select agent Burkholderia pseudomallei. Although increasingly recognized throughout the tropics, melioidosis is hyperendemic in northeast Thailand, where it is tied as the second leading infectious cause of death. Even with appropriate antibiotic treatment, 40% of patients die, many from severe sepsis. Of survivors, about 10% relapse, most in the first year. As for other causes of sepsis, no successful immunomodulatory therapies exist. Melioidosis is therefore a major public health threat in Thailand for which new therapies are urgently needed. We have implemented a highly successful Thai-US collaboration to elucidate mechanisms of host defense in human melioidosis for nearly eight years. Our whole exome sequencing studies of bacteremic patients have identified candidate genes and inflammatory pathways that may determine outcome in melioidosis. Our collaborators on this proposal, Dr. Chaussabel and Dr. Lertmongkolchai, have analyzed the blood transcriptome to create signatures that distinguish melioidosis from other causes of sepsis and identify biological pathway activation that is unique to melioidosis. While the human inflammatory response in melioidosis remains poorly understood, our preliminary results spotlight the promise of the application of advanced technologies to melioidosis. We propose a Melioidosis ICIDR that intensifies existing international scientific relationships by applying state-of-the-art technologies to comprehensively elucidate the immunologic and inflammatory mechanisms underlying the pathogenesis of melioidosis and poor response to therapies. We will augment our whole exome sequencing analyses with whole transcriptome RNA sequencing and high-throughput single cell polychromatic flow cytometry for sophisticated immunophenotyping of melioidosis patients. Designed around a prospective, multi-center longitudinal cohort study of melioidosis with detailed clinical and biological phenotyping, and expert-supported in-country analysis of all resulting data, the proposal will directly enhance Thai melioidosis research capacity. Our aims are to 1) identify host inflammatory changes in acute melioidosis that elucidate pathogenesis and predict death, 2) identify immunological mechanisms that permit relapse, and 3) validate newly identified genetic determinants of survival in melioidosis. Beyond the scientific aims addressed in this application, the proposal establishes a unique and durable melioidosis research platform headquartered in the optimal location for clinical melioidosis research, with tremendous potential to impact the public health o Thais and global citizens alike.