Helminths and the Immune System : Regulation, Regulators and Immunity. (360G-Wellcome-106122_Z_14_Z)

Over the past 10 years my laboratory has played a leading international role in establishing that immunoregulatory mechanisms underpin susceptibility to helminth parasite infection, with resistance in mouse models induced by depletion of Tregs [1,2] and susceptibility promoted by multiple regulatory populations [3]. We have been key in linking regulatory networks to suppression of bystander reactivities, for example in allergy [4] and autoimmunity [5], providing a mechanistic framework for the hygiene hypothesis which posits that active infection can protect the host from immunological disorders [6]. Human studies confirm that asymptomatic carriers of helminth infection display a dominant regulatory phenotype, which is deficient in cases with pathological outcomes [7,8], more firmly linking immunoregulation with active helminth infection. Our laboratory has also been leading these studies into a new, more defined and translational phase, identifying molecular regulators from parasite s that modulate host immunity (for example [9,10]). We focus on products secreted from the parasite that counteract key steps in the host response, and which are likely to offer new avenues to combat non-communicable immunopathologies [11], and study a model, the gastrointestinal helminth Heligmosomoides polygyrus, which is exquisitely co-adapted to the murine immune system. H.polygyrus drives a suite of immunomodulatory changes in vivo [12]. We have now fully characterised its transcriptome a nd secreted proteome [13,14] and most recently discovered it releases microRNA-loaded exosomes able to modulate host cells [15]. H.polygyrus is also closely related to the two human hookworms which infect ~800 million people, one of which (Necator americanus) now has a complete genome sequence [16]. As immunomodulation underpins host susceptibility to infection, we have in addition developed a vaccination strategy that blocks parasite-induced regulation and permits immunity to develop [14,17]. This work has highlighted how little is yet known about the mechanistic pathways of immunity to helminths, and offers a direct opportunity to address this deficiency. As summarised in Fig. 1 my research thus targets the following questions: (1) What molecular players from parasites mediate immune regulation, and can they alleviate immunopathology in allergy and colitis? (2) Do helminth-derived exosomes modulate host immunity? (3) Can we learn from vaccination to build a protective anti -helminth effector cell?