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

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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.