Development of novel therapeutics for Babesia microti infection

描述（由申请人提供）：微巴贝虫是一种新出现的人类病原体，也是人类巴贝虫病的主要原因，巴贝虫病是美国流行的一种类似疟疾的疾病。该病原体通过蜱病媒介肩胛骨伊蚊和从无症状微螺旋体感染的献血者输血传播给人类。巴贝斯虫病是一个主要的公共卫生问题，因为面临严重疾病风险的人口（50岁以上和免疫系统受损的任何年龄的人）正在增加。目前推荐阿奇霉素+阿托伐醌或克林霉素+奎宁联合用药。由于这些药物组合具有已知的抗疟疾活性，因此首先对其抗巴贝虫活性进行了评估。使用这些药物和其他支持性措施（如换血），需要住院治疗的感染患者死亡率为9%，免疫功能低下的宿主死亡率接近28%。存活下来的患者可能会经历一年多的复发性寄生虫病，需要更长时间的治疗。尽管药物治疗，巴贝斯虫病仍然存在的原因尚不清楚。更好地了解寄生虫的代谢、多样性、毒力和组织分布对于开发更有效的治疗人类巴贝斯虫病的疗法至关重要。为了实现这一目标，我们已经完成了基因组和转录组学分析，并开始了7个微孢子虫临床分离株的基因组注释和代谢机制重建。我们的初步研究结果表明，微孢子虫在菌株之间表现出基因型差异。这些变异可能解释了它们在增殖率和宿主选择性方面的显著差异（小鼠与仓鼠）。我们还确定了两个关键的代谢途径，非甲羟戊酸（MEP）途径和叶酸生物合成途径（FBP），这两个途径可以被FDA批准的药物靶向。为了充分表征这些药物在体内抗微孢子虫感染的效果，我们建立了小鼠微孢子虫感染模型

DESCRIPTION (provided by applicant): The apicomplexan intraerythrocytic parasite Babesia microti is an emerging human pathogen and the primary cause of human babesiosis, a malaria-like illness endemic in the United States. The pathogen is transmitted to humans by the tick vector, Ixodes scapularis, and by transfusion of blood from asymptomatic B. microti-infected donors. Babesiosis is a major public health concern because the population at risk for severe disease (people over the age of 50 and of any age with compromised immune systems) is increasing. Presently, drug combinations of azithromycin+atovaquone or clindamycin+quinine are recommended therapies. These drug combinations were first evaluated for their anti-babesia activity because of their known antimalarial activity. With these drugs and other supportive measures such as exchange transfusion, the mortality rate is 9% in infected patients requiring hospitalization and approaches 28% in immunocompromised hosts. Patients who survive may experience recrudescent parasitemia for more than a year, requiring more prolonged therapy. The reasons that Babesia can persist despite drug therapy remain unknown. A better understanding of the parasite metabolism, diversity, virulence and tissue distribution are critical for the development of more effective therapies for treatment of human babesiosis. Towards this goal, we have completed genomic and transcriptomic analyses and initiated thorough annotation of the genomes and reconstruction of the metabolic machineries of seven B. microti clinical isolates. Our preliminary findings indicate that B. microti exhibits genotypic variations among strains. These variations may account for their notable differences in rate of proliferation and host selectivity (mice vs hamsters). We have also identified two key metabolic pathways, the non-mevalonate (MEP) pathway and the folate biosynthesis pathway (FBP), which can be targeted by drugs already approved by the FDA. In order to fully characterize the efficacy of these drugs against B. microti infection in vivo, a mouse model of B. microti infection must be more clearly defined in terms of sites of parasite persistence that may lead to recrudescence of parasitemia. Accordingly, this proposal aims to (1) define in mice the kinetics of parasitemia and sites of persistence of two prototype B. microti strains isolated from non-immunocompromised patients who experienced mild or severe disease; and (2) assess the efficacy of drugs that target the MEP and FBP pathways of B. microti to resolve parasitemia and eliminate infection. Successful completion of these exploratory studies will help define mechanisms underlying B. microti pathogenesis and set the stage for future clinical studies to evaluate the efficacy of these drugs for treatment of human babesiosis in situations when current therapies fail.