Investigating naturally occurring regulation of human IgE-mediated hypersensitivity using hookworm-schistosome co-infection

钩虫是地球上最常见的传染病之一，估计全世界有5.76亿至7.4亿人感染。作为流行地区的一种祸害，几乎没有证据表明自然产生的针对它们的免疫力。通过分泌的产物，钩虫可以有效地调节免疫系统，使它们在人类宿主体内长寿。即使它们在进食时与人类宿主的肠道有组织损伤的相互作用，也会发生这种情况。调节免疫系统的机制对钩虫可能是特异性的，也可能是非特异性的；后者导致旁观者效应，即免疫系统对其他触发因素的反应被下调。这些旁观者效应可能是在钩虫感染流行的社区中过敏性疾病发病率极低的原因之一，尽管已经尝试破译钩虫对过敏反应的调节作用，但由于钩虫流行地区患有过敏性疾病的个体稀缺，这些研究往往受到阻碍。对另一种流行的蠕虫感染，曼氏血吸虫的反应可以在严格的监管下进行。对于每天数以百计的虫卵的反应尤其如此，大量虫卵被困在宿主组织中，使宿主暴露于启动免疫反应的分子中。因此，调节对这些分子的反应可以防止严重的免疫驱动病理的发展。相比之下，寄生在血液中的成年血吸虫会进行免疫逃避，在蠕虫死亡时，免疫系统的隐蔽性触发只会间歇性地暴露于宿主。这种间断性接触可产生IgE介导的免疫；导致过敏反应的相同免疫机制，事实上，在对垂死的成虫的反应中观察到的与ige相关的机制与在过敏性疾病中观察到的机制有许多共同的特征。过去十年来，我们一直在乌干达马伊格区开展关于人类蠕虫感染的免疫反应的研究，在那里，尽管定期进行大规模药物治疗，钩虫和曼索尼梭菌感染的负担仍然很高。在我们的研究中，我们观察到钩虫对过敏相关反应的免疫调节也包括IgE介导的反应，这些反应是在对曼氏梭菌感染的免疫发展过程中触发的。在此，我们拟研究钩虫对抗血吸虫免疫应答的调节作用，探讨这种调节作用的靶点和可能的机制。钩虫的这种调节对感染这两种蠕虫的人群具有重大影响，特别是在控制规划的药物给药时间表方面。如果要充分实现抗血吸虫治疗的免疫增强治疗效果，可能需要在血吸虫治疗之前进行钩虫治疗。通过与过敏的共同特征，该研究还将深入了解钩虫如何调节过敏反应，为目前估计其日常生活受到过敏性疾病不利影响的数亿人开发治疗方法提供有益的知识。随着城市化和发展的西方生活方式在全球范围内的扩展，受过敏影响的个体数量不断增加，这一知识至关重要。

Hookworms are some of the most prevalent infections on earth, estimated to infect between 576 and 740 million people worldwide. A scourge in endemic regions, there is little evidence that naturally occurring immunity develops against them. Through secreted products hookworms potently modulate the immune system, providing them with longevity within the human host. This occurs even though they have tissue damaging interactions with the human host's gut while they feed. The mechanisms by which the immune system is modulated can be specific to hookworms or non-specific; the latter resulting in bystander effects, in which the response to other triggers of the immune system are down regulated. These bystander effects are one of the likely reasons for the very low incidence of allergic disease in communities where hookworm infection is endemic, and although attempts have been made to decipher the modulation exerted by hookworm on allergic responses, these are often hindered by the scarcity of individuals with allergic disease in hookworm endemic areas.Responses to another prevalent worm infection, Schistosoma mansoni, can be under tight regulation. This is particularly true of the response to eggs which are deposited in their hundreds every day, a substantial number becoming trapped in the host tissue, exposing the host to molecules that initiate an immune response. Thus regulation of the response to these molecules prevents development of severe immune driven pathology. In contrast, the blood-dwelling adult schistosome worms immune evade, with cryptic triggers of the immune system only intermittently being exposed to the host upon worm death. This intermittent exposure allows the development of IgE mediated immunity; the same immune mechanism that causes allergic reactions, and indeed these IgE-assocatiated mechanisms observed in response to dying adult worms share many features with those observed in allergic diseases. In Mayuge District, Uganda, where for the last decade we have been conducting research on the immune response to human worm infections, the burden of both hookworm and S. mansoni infection has remained high despite regular rounds of mass drug treatment. During our studies we have observed that the immune modulation of allergy associated responses by hookworm also encompasses the IgE mediated responses that are triggered during the development of immunity to S. mansoni infection. Here we propose to study the modulation of the anti-schistosome immune response by hookworm, investigating the targets of this modulation and the potential mechanisms by which hookworms exert their effects. This modulation by hookworm has major implications for the populations who are infected with these two worms, particularly in the context of drug administration schedules of the control programme. It may be that hookworm treatment needs to be administered prior to schistosome treatment, if the immune boosting treatment effects of anti-schistosome treatment are to be fully realised. Through the shared features with allergy, the study will also provide insight into how hookworm may modulate allergic responses, beneficial knowledge for developing treatments for the hundreds of million individuals currently estimated to have their daily lives adversely affected by allergic disease. This knowledge is critical as the number of individuals affected by allergy is constantly growing as our western lifestyle of urbanisation and development expands across the globe.