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

描述(由申请人提供) 摘要：结核病每年导致近200万人死亡。长期的治疗方案会导致患者的不依从性，从而导致耐药性的发展。艾滋病毒/艾滋病大流行进一步加速了广泛耐药(XDR)菌株的出现，这些菌株既是致命的，也是可传播的。迫切需要新的治疗方法。现有的抗结核病疗法针对的是这种细菌。这个项目将利用我最近关于宿主对结核病易感性的发现，开发基于特定的、由基因决定的宿主免疫途径的新的治疗策略。通过在斑马鱼中进行的大规模正向遗传筛选，我发现白三烯A4水解酶(LTA4H)基因在控制结核病易感性方面起着关键作用。在鱼类和哺乳动物中，LTA4H酶起到变阻器的作用，控制特定的促炎和抗炎二十烷类化合物的相对水平。我们发现，人类人群中常见的LTA4H基因多态性控制着结核病和麻风的易感性。携带LTA4H基因导致中等水平炎症的人可以预防结核病。有趣的是，具有最大促炎反应的LTA4H基因携带者的表现与那些导致炎症不足的基因携带者一样差。这些发现表明，我们对结核病易感性的理解是一种全新的范式。人们容易过敏有两个截然相反的原因--对感染的反应不足或过度活跃的炎症反应，这对宿主同样有害。这项提案将探索这样一种假设，即针对常见基因类型的宿主定向治疗将提供一种根本性的抗击结核病的新方法。在我的假设的有力支持下，我发现人类LTA4H基因决定了对结核病脑膜炎标准辅助治疗的临床反应性。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二十烷基类途径的药物，作为一种全新的抗结核病治疗途径。最后，低炎症和高炎症状态的建模将为整个动物在体内筛选靶向宿主二十烷类途径的新药提供一个平台。 公共卫生相关性：这项提案旨在开发治疗结核病的新方法。结核病每年导致近200万人死亡，据估计感染了世界三分之一的人口。根据患者的基因型定制有效的辅助疗法可能会对结核病脑膜炎的治疗产生直接影响，结核病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.