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.

世界上超过 1.2 亿最贫困人口面临遭受寄生丝虫线虫影响的高风险——班氏丝虫、马来丝虫和帝汶丝虫——它们生活在淋巴系统中，引起人类淋巴丝虫病，俗称“淋巴丝虫病”。例如，象皮病以及其他严重疾病（河盲症）是由以下原因引起的。盘尾丝虫寄居在皮下结节内，释放微丝蚴 (Mf)，导致眼部或皮肤病变，包括失明。不幸的是，国际控制计划的重点是控制感染的传播，该计划的目标是 15 亿有感染危险的人。 ，用于大规模药物管理举措（伊维菌素）的治疗仅产生微丝虫杀作用 - 它们阻止传播，但对成虫寄生虫没有影响。它们还需要每年长期使用。管理，在罗阿罗阿流行地区是禁忌的，儿童和孕妇除外，并促进丝虫线虫的耐药性，这些限制表明迫切需要开发新的抗丝虫药物，特别是杀大丝虫药物。杀死成虫。临床研究表明，使用沃尔巴克氏体（丝虫线虫的共生细菌）作为对抗人类丝虫感染的新型化疗靶标具有独特的潜力。为了探索这种潜力，我们引入了一种新的方法：以宿主（寄生虫）为导向的治疗，诱导宿主先天防御并迫使丝虫线虫消除其内共生体。打算利用自噬这一真核细胞的机制来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、该过程对于细菌-丝虫共生至关重要，其改变杀死了沃尔巴克氏体，从而杀死了蠕虫本身。我们获得了证据，表明氯硝柳胺（自噬诱导剂）可激活寄生虫中的自噬，显着减少细菌数量并产生胚胎抑制效应。我们的项目将确定自噬诱导剂可以作为目标 1 中的候选杀丝虫药物，以证明自噬诱导剂在体内有效。我们将评估氯硝柳胺在丝虫寄生虫中的功效，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）对成年丝虫寄生虫的作用，并比较它们对丝虫寄生虫的作用。 Aim 1 中的沃尔巴克氏体负载和成虫适应性将导致选择最佳命中（甚至比 In Aim 更好）。 2、最好的 2 种候选药物将在我们的体内 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的新型微丝虫杀剂，我们相信，这一举措将产生一类新的活性化合物并开放。重新利用药物的前景，用作当前抗丝虫治疗的替代品或与当前抗丝虫治疗结合使用。