Mechanisms of immune regulatory and inflammatory host-parasite interaction in neurocysticercosis

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Regulation of inflammatory, infection-triggered processes in the brain constitutes a central mechanism to control devastating disease manifestations such as epilepsy. In neurocysticercosis (NCC), the most common cause of epilepsy, especially in children, in Sub-Saharan Africa, observational studies implicate the viability of Taenia solium cysts, the larval stage of the helminth in the brain, as a key factor determining the severity of the disease. Decaying cysts are associated with epilepsy or other neurological symptoms, whereas viable cysts remain mostly clinically silent via yet unidentified processes potentially involving Tregs in controlling inflammation. Our current investigations, suggest that the expansion of Tregs via lipid mediators (LMs) in NCC is involved in controlling the inflammatory response both in the CNS and in the periphery during clinically silent T. solium infection. We recently demonstrated that the enzyme glutamate dehydrogenase released by viable cysts instructs tolerogenic monocytes to release IL-10 and the lipid mediator PGE2, which act in concert to convert naive CD4+ T cells into CD127-CD25hiFoxP3+CTLA-4+ Tregs. Moreover, while viable cyst products strongly upregulated IL-10 and PGE2 transcription in microglia, unidentified molecule(s) from intravesicular fluid, released during cyst decay, induced proinflammatory microglia and TGF-ß as potential drivers of epilepsy. This proinflammatory potential is further reflected by significant TNF release and marked apoptosis in macrophages and T cells, which warrant further investigation to uncover the specific signaling pathways. Taken together, these data clearly support the hypothesis that viable and degenerating larval cysts harbor distinct immunogenic components that either modulate innate immune cells (microglia, monocytes, macrophages) to instruct the de-novo differentiation of Treg cells or cell apoptosis, brain inflammation and eventually epilepsy by a TGF-beta driven mechanism. In this project we thus aim to (1) uncover the distinct mechanistic pathways and the helminth molecule(s) involved in immune cell apoptosis; (2) identify the nature of the signals (epigenetic, transcriptional) controlling the PGE2-IL-10-Treg axis and the phenotype, and functionality and stability of these Tregs; (3) identify the brain inflammatory and epileptiform potential of the apoptosis inducing helminth molecules in an in vitro brain model employing a unique brain slice culture system. The ultimate goal of this proposal is to translate these findings to human studies and to support the identification of parasitic biomarkers and key immuno-determinants for symptomatic disease which are still urgently in need to support appropriate anti-inflammatory therapeutic approaches.