Harnessing the Host Response to Leptosporisis for Diagnosis and Prognosis

摘要：杜克大学项目4 钩端螺旋体病是一种常见的、具有全球意义的潜在威胁生命的感染。这种细菌是从 各种不同的宿主动物通常通过接触受感染的尿液来感染人类。结果, 钩端螺旋体病是热带地区发烧的主要原因。钩端螺旋体病可引起严重的器官疾病 失败和死亡。虽然感染对抗生素有反应，但由于相似之处，治疗经常被推迟。 与其他发烧原因(如登革热)和当前诊断测试的局限性有关。钩端螺旋体不会成长 在标准的培养介质中，分子病原体检测方法始终存在灵敏度不足的问题。 疾病的病程和急性期的血清学既不敏感又不具特异性。配对(急性和 恢复期)血清可以回顾确认急性感染，但恢复期随访很少。一个 越来越多的证据支持基于分子生物标记物的开发潜力 人类对感染的免疫反应不仅可以检测感染的病原体，还可以预测疾病的严重程度 在传染病方面。 这些“宿主反应”诊断试验的开发和验证需要严格的前瞻性研究 不同地点的钩端螺旋体病，不同菌株的钩端螺旋体在不同的人群中很常见 祖传背景。我们的研究团队有20年在三大洲进行此类研究的经验： 斯里兰卡(Galle)、尼加拉瓜(Leon)和坦桑尼亚(Moshi)，这些国家的钩端螺旋体病流行病学很好 已经成立了。除了相对常见之外，严重的疾病在尼加拉瓜和斯里兰卡也有很好的记录。 斯里兰卡支持开发预测疾病进展的诊断学。我们的团队有广泛的 在生成相关分子数据(基因和蛋白质表达)以及分析、机器- 用于开发多分析物寄主反应分类器的学习工具 感染病程可用于识别和预测钩端螺旋体病的严重程度。该团队还拥有 将这些生物标志物集转换到现有诊断平台的经验。在这个项目中，我们将增加 我们现有的来自三个不同地理位置的样本生物库，以支持开发 钩端螺旋体病特异性分子分类器，用于诊断和预测疾病严重程度。重要的是 关键的初步数据和无与伦比的样本和临床数据生物信息库支持项目4和 与拟议研究计划中的项目1-3协同工作。项目4将由医学博士梅根·E·雷勒领导， 博士，公共卫生硕士。

Abstract: Project 4, Duke University Leptospirosis is a common, potentially life-threatening infection of global significance. The bacteria spread from a variety of different host animals to humans typically through contact with infected urine. As a result, leptospirosis is a leading cause of fever in the tropics. Leptospirosis can cause severe disease resulting in organ failure and death. Although the infection is responsive to antibiotics, treatment is often delayed due to similarities with other causes of fever (e.g., dengue) and limitations of current diagnostic tests. Leptospira spp. do not grow in standard culture media, molecular pathogen detection methods suffer from insufficient sensitivity throughout the course of the disease, and acute-phase serology is both insensitive and non-specific. Paired (acute and convalescent) sera can confirm acute infection retrospectively, but convalescent follow-up is infrequent. A growing body of evidence supports the potential for the development of molecular biomarkers based on the human immune response to the infection to not only detect infectious pathogen but also predict disease severity in infectious diseases. The development and validation of these “host response” diagnostic tests requires rigorous prospective studies of leptospirosis in diverse locations where different strains of the bacteria are common in people of different ancestral backgrounds. Our research team has 20 years of experience conducting such studies on 3 continents: Sri Lanka (Galle), Nicaragua (Leon), and Tanzania (Moshi) where the epidemiology of leptospirosis is well established. In addition to being relatively common, severe disease is well documented in Nicaragua and Sri Lanka to support development of diagnostics predictive of disease progression. Our team has extensive experience in generating the relevant molecular data (gene and protein expression) and the analytical, machine- learning tools for developing multi-analyte host response classifiers for pathogen differentiation across the course of infection which can be applied to identify and predict the severity of leptospirosis. The team also has experience translating these sets of biomarkers onto existing diagnostic platforms. In this project, we will add to our existing biorepository of samples from three geographically diverse locations to support the development of leptospirosis-specific molecular classifiers for both diagnosis and prediction of disease severity. Importantly, critical preliminary data and an unparalleled biorepository of samples and clinical data support Project 4 and synergize with Projects 1-3 in the proposed research program. Project 4 will be led by Megan E. Reller, MD, PhD, MPH.