Le Gros Laboratory, Malaghan Institute of Medical Research, Wellington, New Zealand.
Department of Medicine, University of Otago, Wellington, New Zealand.
Gut Microbes. 2024 Jan-Dec;16(1):2416517. doi: 10.1080/19490976.2024.2416517. Epub 2024 Oct 16.
Infecting humans with controlled doses of helminths, such as human hookworm (termed hookworm therapy), is proposed to prevent or treat various intestinal and extraintestinal diseases. However, full-scale clinical trials examining hookworm therapy are limited by the inability to scale-up the production of hookworm larvae to infect sufficient numbers of patients. With the aim of overcoming this challenge, this study infected four healthy individuals with hookworm larvae that had been reanimated from cryopreserved eggs to examine their viability and immunogenicity. We demonstrate that reanimated cryopreserved hookworm larvae establish a viable hookworm infection and elicit a similar immune response to larvae cultured from fresh stool. Furthermore, a refined understanding of the therapeutic mechanisms of hookworm is imperative to determine which diseases to target with hookworm therapy. To investigate potential therapeutic mechanisms, this study assessed changes in the immune cells, microbiome, and plasma metabolome in the four healthy individuals infected with cryopreserved hookworm larvae and another nine individuals infected with larvae cultured from freshly obtained stool. We identified potential immunoregulatory mechanisms by which hookworm may provide a beneficial effect on its host, including increased expression of CTLA-4 on regulatory T cells (Tregs) and upregulation of tryptophan metabolism. Furthermore, we found that a participant's baseline microbiome predicted the severity of symptoms and intestinal inflammation experienced during a controlled hookworm infection. In summary, our findings demonstrate the feasibility of full-scale clinical trials examining hookworm therapy by minimizing the reliance on human donors and optimizing the culturing process, thereby enabling viable hookworm larvae to be mass-produced and enabling on-demand inoculation of patients. Furthermore, this study provides insights into the complex interactions between helminths and their host, which could inform the development of novel therapeutic strategies.
用控制剂量的寄生虫感染人类，如人体钩虫（称为钩虫疗法），被提议用于预防或治疗各种肠道和肠道外疾病。然而，全面的临床试验检查钩虫疗法受到无法扩大钩虫幼虫的生产规模以感染足够数量的患者的限制。本研究旨在克服这一挑战，用从冷冻保存的虫卵中复活的钩虫幼虫感染了四名健康个体，以检查它们的生存能力和免疫原性。我们证明，复活的冷冻保存的钩虫幼虫可以建立一个可行的钩虫感染，并引起类似于从新鲜粪便中培养的幼虫的免疫反应。此外，深入了解钩虫的治疗机制对于确定用钩虫疗法治疗哪些疾病至关重要。为了研究潜在的治疗机制，本研究评估了感染冷冻保存钩虫幼虫的四名健康个体和感染从新鲜粪便中培养的幼虫的另外九名个体的免疫细胞、微生物组和血浆代谢组的变化。我们确定了钩虫可能对其宿主产生有益影响的潜在免疫调节机制，包括调节性 T 细胞（Tregs）上 CTLA-4 的表达增加和色氨酸代谢的上调。此外，我们发现参与者的基线微生物组预测了在受控钩虫感染期间经历的症状和肠道炎症的严重程度。总之，我们的研究结果表明，通过最小化对人类供体的依赖和优化培养过程，可以实现全面的临床试验检查钩虫疗法，从而可以大规模生产可行的钩虫幼虫，并能够按需接种患者。此外，本研究提供了对寄生虫与其宿主之间复杂相互作用的深入了解，这可能为新的治疗策略的发展提供信息。
