Modulating Eicosanoids to Treat Tuberculosis: Personalized, Host-directed Therapy

描述（由申请人提供） 翻译后摘要：结核病（TB）每年造成近两百万人死亡。长期的治疗方案导致患者不依从，从而产生耐药性。艾滋病毒/艾滋病的流行进一步加速了广泛耐药（XDR）菌株的出现，这些菌株既致命又可传播。迫切需要新的治疗方法。现有的抗结核病疗法针对细菌。这个项目将利用我最近关于宿主对结核病易感性的发现，以靶向特定的、遗传决定的宿主免疫途径为基础，开发新的治疗策略。 通过在斑马鱼中进行大规模的正向遗传筛选，我确定了白三烯A4水解酶（lta 4 h）基因在控制结核病易感性中的关键作用。在鱼类和哺乳动物中，LTA 4 H酶起变阻器的作用，控制特定的促炎和抗炎类花生酸的相对水平。我们发现，在人群中常见的LTA 4 H多态性控制结核病和麻风病的易感性。具有导致中等水平炎症的LTA 4 H基因型的人可以免受结核病的侵害。有趣的是，具有最大化促炎反应的LTA 4 H基因型的个体与具有导致炎症不足的基因型的个体一样表现不佳。这些发现为我们理解结核病易感性提供了一个全新的范例。人们过敏有两个截然相反的原因--对感染的反应不足，或者对宿主同样有害的过度炎症反应。 该提案将探索针对常见基因型的个体化宿主导向疗法将提供对抗结核病的全新方法的假设。我发现人类LTA 4 H基因型决定了结核性脑膜炎标准连续治疗的临床反应性，这有力地支持了我的假设。我们将使用斑马鱼模型来了解这些低炎症和高炎症状态对结核病发病机制和疾病结局的影响。我们将研究专门针对宿主类花生酸途径的药物，作为抗结核治疗的一种全新途径。最后，低炎症和高炎症状态的建模将为整个动物体内筛选靶向宿主类花生酸途径的新药提供平台。 公共卫生相关性：该提案旨在开发治疗结核病的新方法，结核病每年造成近200万人死亡，估计感染世界三分之一的人口。根据患者基因型定制有效的连续治疗方法可能会对结核性脑膜炎的治疗产生直接影响，结核性脑膜炎是一种特别致命的疾病。

DESCRIPTION (Provided by the applicant) Abstract: Tuberculosis (TB) kills nearly two million people annually. Long treatment regimens result in patient non-compliance, and the consequent development of drug-resistance. The HIV/AIDS pandemic has further hastened the emergence of extensively drug-resistant (XDR) strains that are both lethal and transmissible. New therapeutic approaches are urgently needed. Existing anti-TB therapies target the bacteria. This project will exploit my recent discoveries about host susceptibility to TB to develop novel therapeutic strategies based on targeting specific, genetically-determined host immune pathways. Through a large-scale forward genetic screen in the zebrafish I identified the leukotriene A4 hydrolase (lta4h) gene as critical in controlling susceptibility to TB. In fish and in mammals, the LTA4H enzyme functions as a rheostat, controlling relative levels of specific pro- and anti- inflammatory eicosanoids. We found that common LTA4H polymorphisms in human populations control susceptibility to TB and leprosy. People with LTA4H genotypes that result in intermediate levels of inflammation are protected from TB. Intriguingly, individuals with LTA4H genotypes that maximize pro-inflammatory responses fared just as poorly as those with genotypes resulting in inadequate inflammation. These findings suggest an entirely new paradigm in our understanding of TB susceptibility. People are hypersusceptible for two diametrically opposed reasons - an inadequate response to the infection or an overexuberant hyperinflammatory response that is equally detrimental to the host. This proposal will explore the hypothesis that host-directed therapies personalized to common genotypes will provide a fundamentally new approach to combating TB. In strong support of my hypothesis, I have found that human LTA4H genotypes determine clinical responsiveness to standard adjunctive therapy for TB meningitis. We will use the zebrafish model to understand the repercussions of these hypo- and hyperinflammatory states for TB pathogenesis and disease outcome. We will examine drugs that specifically target host eicosanoid pathways as an entirely new avenue of anti-TB treatment. Lastly, the modeling of hypo- and hyperinflammatory states will provide a platform for whole animal, in vivo screening for new drugs that target host eicosanoid pathways. Public Health Relevance: This proposal aims to develop new approaches to treating tuberculosis, a disease that kills nearly two million people annually and is estimated to infect one third of the world's population. The tailoring of effective adjunctive therapies based on patient genotype could have immediate impact on the treatment of TB meningitis, a particularly deadly form of the disease.