Activating autophagy in filarial worms to identify novel macrofilaricides

激活丝虫中的自噬以鉴定新型大丝虫杀剂

• 批准号: 10040523
• 负责人: Sara Lustigman
• 金额: $ 23.79万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-19 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040523
• 关键词: Adult; Affect; Age; Albendazole; Anaplasma; Animal Model; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Area; Autophagocytosis; Bacteria; Blindness; Brugia; Brugia malayi; Cells; Cessation of life; Chemicals; Child; Citrates; Clinical Research; Country; Cytoplasm; Data; Defense Mechanisms; Dermal; Development; Diethylcarbamazine; Dose; Doxycycline; Drug Design; Drug Targeting; Drug resistance; Drug usage; Ehrlichia; Elephantiasis; Embryonic Development; Environment; Eukaryotic Cell; Female; Fertility; Filaria bancrofti; Filarial Elephantiases; Future; Goals; Grant; Human; In Vitro; Infection; Insecta; International; Intestinal Volvulus; Ivermectin; Jird; Libraries; Ligands; Loa loa; Lymphatic System; Modeling; Natural Product Drug; Nematoda; Ocular Onchocerciasis; Onchocerca volvulus; Onchocerciasis; Parasites; Pathology; Pathway interactions; Pharmaceutical Preparations; Phylogenetic Analysis; Play; Pregnant Women; Process; Reproduction; Rickettsia; Role; Subcutaneous Nodule; Symbiosis; Testing; Virus; Visual impairment; Wolbachia; World Health Organization; base; cell motility; disability; endosymbiont; filaria; fitness; high risk; human pathogen; in vitro Assay; in vivo; mutualism; new therapeutic target; novel; novel strategies; pathogen; programs; symbiont; translational approach; transmission process

More than 120 million of poorest in the world are at high risk of suffering the debilitating effects of the parasitic filarial nematodes⎯ Wuchereria bancrofti, Brugia malayi, and B. timori ⎯ that live in the lymphatic system and cause human lymphatic filariasis, commonly known as elephantiasis, as well as other severe pathologies. Onchocerciasis (river blindness), for one, is caused by Onchocerca volvulus, which resides within subcutaneous nodules and releases the microfilariae (Mf) that are responsible for ocular or dermal pathologies, including blindness. International control programs, which target 1.5 billion people in danger of infection, focus on controlling the transmission of infections. Unfortunately, the treatments used for mass drug administration initiatives (ivermectin) produce only microfilaricidal effects – they block transmission but have no effect on the adult parasites. They also require long-term yearly administration, are contraindicated in areas co-endemic with Loa loa, exempt children and pregnant women, and promote drug resistance in filarial nematodes. Together, these limitations point to a crucial need for the development of new anti-filarial drugs, specifically macrofilaricidal drugs that kill adult worms. Recent data demonstrate the unique potential of using Wolbachia, the mutualistic bacteria of filarial nematodes, as a novel chemotherapeutic target against human filarial infections. Clinical studies showed that the administration of antibiotics (doxycycline) kills endosymbionts and causes macrofilaricidal effects. To explore this potential, we introduce a novel approach: a host(parasite)- oriented treatment that induces a host innate defense and forces filarial nematodes to eliminate their endosymbiont. We intend to take advantage of autophagy, a mechanism of eukaryotic cells to maintain a healthy intracellular environment and protect cells against intracellular invaders (e.g., bacteria, virus es). The process is essential for bacteria-filaria symbiosis and its alteration killed Wolbachia and, consequently, the worm itself. We obtained proof, that niclosamide (autophagy inducer) activates autophagy in parasites, significantly decreases number of bacteria and causes embryostatic effect in adult worms. Our project will determine that the autophagy inducers can be candidate macrofilaricidal drugs. In Aim 1, to prove that autophagy inducers are effective in vivo against filarial parasites and can be used as macrofilaricidal drugs, we will evaluate the efficacy of niclosamide in Brugia infected jirds. In parallel, we will test the other 23 repurposed drugs (known autophagy inducers) on adult Brugia parasites in vitro and compare their effects on the Wolbachia load and adult worm fitness. The in vitro assays in Aim 1 will result in the selection of the best hits (even better than niclosamide). In Aim 2, the best 2 candidates will be validated in our in vivo Brugia/jird model of infection. Our end goal is to identify effective new microfilaricides that interfere with symbiosis. This initiative, we believe, will yield a new class of active compounds and open perspectives for repurposed drugs, for use as alternatives to or in combination with current anti-filarial treatments.

世界上有超过1.2亿最贫穷的人有寄生丝状丝状线虫的衰弱影响的高风险。 OnChocerciasis（河流失明）是由OnChocerca Volvulus引起的，该chocerca volvulus在皮下结节内的住所并释放了负责眼部或真皮病理的微毛皮菌（MF），包括失明。国际控制计划针对有15亿人有感染危险的人，重点是控制感染的传播。不幸的是，用于大规模药物管理倡议（IPERMECTIN）的处理方法仅产生微椰胶脂效应 - 它们阻止了传播，但对成年寄生虫没有影响。他们还需要每年长期给药，在与LOA LOA，豁免儿童和孕妇共内多的地区禁忌，并在丝状线虫中促进耐药性。总之，这些局限性表明，需要开发新的抗狂药，特别是杀死成人蠕虫的大脂肪虫药物。最近的数据表明，使用Wolbachia（丝状线虫的互助细菌）作为对人丝状感染的新型化学治疗靶标的独特潜力。临床研究表明，抗生素的给药（强力霉素）杀死内共生菌，并引起大脂肪性作用。为了探索这一潜力，我们引入了一种新颖的方法：一种宿主（寄生虫）的治疗方法，该治疗诱导宿主先天防御和迫使丝状线虫消除其内共生菌。我们打算利用自噬，这是一种真核细胞维持健康的细胞内环境并保护细胞免受细胞内入侵者（例如细菌，病毒）的机制。这一过程对于细菌 - 捕虫共生及其变化至关重要，因此杀死了沃尔巴基亚，因此是蠕虫本身。我们获得了证据，表明烟酰胺（自噬诱导剂）激活寄生虫的自噬，大大减少了细菌的数量，并在成年蠕虫中引起胚胎效应。我们的项目将确定自噬诱导剂可以是候选大写药物。在AIM 1中，为了证明自噬诱导剂在体内对丝状寄生虫有效，并且可以用作大氟霉素药物，我们将评估烟酰胺在Brugia感染的Jirds中的有效性。同时，我们将在体外测试其他23种重新利用的药物（已知的自噬诱导剂），并在体外测试成年的Brugia寄生虫，并比较它们对Wolbachia负荷和成人蠕虫健身的影响。 AIM 1中的体外测定将导致选择最佳命中率（甚至比烟酰胺更好）。在AIM 2中，最好的2个候选者将在我们的体内Brugia/Jird感染模型中得到验证。我们的最终目标是确定干扰共生的有效新微验证剂。我们认为，这项倡议将产生一类新的活性化合物和开放式药物的开放式观点，以用作或与当前的抗生治疗相结合的替代品。