Role and mechanism of action of glutamate dehydrogenase in helminth-driven regulation of eicosanoids and type 2 immunity

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More than 500 million people worldwide are affected by chronic inflammatory airway diseases such as allergic asthma or nasal polyps. Unfortunately, a significant part of these patients suffers from therapy resistant disease. In this context, it is intriguing that worm parasites can produce molecules, which suppress allergic inflammation. In the proposed project, we aim to mechanistically characterize immuneregulatory effects and molecules from a worm parasite with the ultimate aim to harness this potential for the therapy of airway inflammation. So far, we could show that a larval extract of the intestinal parasite Heligmosomoides polygyrus bakeri (“HpbE”) induces a macrophage phenotype that is able to suppress allergic inflammation. In particular, we could show that HpbE modifies the lipid mediator metabolism of macrophages to induce a profile, which is dominated by regulatory/ anti-inflammatory mediators such as prostaglandin E2 (PGE2). Moreover, macrophages, which lack the enzyme cyclooxygenase 2 (COX2), were no longer able to suppress allergic immune responses. Furthermore, we could identify first molecules and mechanisms that are responsible for the immuneregulatory actions of HpbE. In the continuation proposal, we now aim to validate the immuneregulatory effects of our major candidate protein (Hpb glutamate dehydrogenase, GDH) and to elucidate its mechanism of action. At the time of submission, we are optimizing the expression and purification of Hpb GDH to allow for its recombinant production in good quality and quantity. We have also raised a monoclonal antibody against Hpb GDH. With these tools in hand, we aim to study if and how GDH from the parasite is shuffled to host immune cells and if this results in a shift in the lipid mediator- and glutamine- metabolism. The efficacy of Hpb GDH and its mechanism(s) of action will then be assessed in mouse models of allergy and helminth (Hpb) infection as well as in human macrophages.Through transcriptional (RNAseq) profiling, we have obtained first hints to a role for epigenetic mechanisms (histone modifications) in the immuneregulatory effects of the total extract (HpbE). By performing epigenetic analyses (ChIPseq) and by blocking potential mechanistic targets (e.g. HDACs), we now aim to investigate how histone modifications may contribute to the modulation of the lipid mediator metabolism and effector functions of macrophages by HpbE and Hpb GDH. In summary, our work will contribute to a better understanding of the regulation of innate immune responses in the context of allergic inflammation and may foster the translation into novel therapies.