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

钩虫是地球上最普遍的感染之一，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免疫力对它们产生了影响。通过分泌的产品钩虫有力地调节免疫系统，使它们在人类宿主中长寿。即使它们在进食时与人类宿主的肠道发生组织破坏性相互作用，也会发生这种情况。调节免疫系统的机制可以是特异性的或非特异性的;后者导致旁观者效应，其中对免疫系统的其他触发物的反应被下调。这些旁观者效应是钩虫感染流行的社区中过敏性疾病发病率极低的可能原因之一，尽管已经尝试破译钩虫对过敏反应的调制，但这些往往受到钩虫流行地区过敏性疾病个体稀缺的阻碍，对另一种流行蠕虫感染，曼氏血吸虫的反应可能受到严格的调控。这一点在对每天数百个卵的反应中尤其如此，大量卵被困在宿主组织中，使宿主暴露于引发免疫反应的分子中。因此，对这些分子的应答的调节防止了严重免疫驱动病理的发展。相比之下，血栖的成虫寄生虫的免疫逃避，与神秘的触发免疫系统只有间歇性地暴露于主机后蠕虫死亡。这种间歇性暴露允许IgE介导的免疫力的发展;引起过敏反应的相同免疫机制，并且实际上在对垂死蠕虫的反应中观察到的这些IgE相关机制与在过敏性疾病中观察到的那些机制具有许多特征。在乌干达的Mayuge地区，在过去的十年里，我们一直在进行对人类蠕虫感染的免疫反应的研究，钩虫和S。尽管定期进行大规模药物治疗，但曼索尼感染率仍然很高。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，这些反应在对S.曼氏感染。在这里，我们建议研究钩虫的抗寄生虫免疫反应的调制，调查这种调制的目标和钩虫发挥其作用的潜在机制。钩虫的这种调节对感染这两种蠕虫的人群具有重大影响，特别是在控制方案的药物管理时间表的背景下。如果要完全实现抗寄生虫治疗的免疫增强治疗效果，可能需要在寄生虫治疗之前给予钩虫治疗。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。随着西方城市化和发展的生活方式在地球仪上的扩展，受过敏影响的个体数量不断增加，因此这一知识至关重要。

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.