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

调节大脑中的炎症、感染触发的过程构成了控制癫痫等破坏性疾病表现的中心机制。在撒哈拉以南非洲地区，神经囊虫病（NCC）是癫痫最常见的原因，特别是儿童，观察性研究表明，脑内蠕虫幼虫阶段的猪带绦虫囊肿的生存能力是决定疾病严重程度的关键因素。腐烂的囊肿与癫痫或其他神经系统症状有关，而存活的囊肿通过尚未确定的过程保持临床沉默，这些过程可能涉及控制炎症。我们目前的研究表明，通过脂质介质（LMs）在NCC中的扩张参与控制临床无症状T细胞期间CNS和外周的炎症反应。寄生虫感染我们最近证明，由活囊肿释放的酶谷氨酸脱氢酶指示致耐受性单核细胞释放IL-10和脂质介质PGE 2，其协同作用将初始CD 4 + T细胞转化为CD 127-CD 25 hiFoxP 3 +CTLA-4+ T细胞。此外，虽然活的囊肿产物强烈上调小胶质细胞中的IL-10和PGE 2转录，但来自囊内液的在囊肿衰变期间释放的未鉴定分子诱导促炎性小胶质细胞和TGF-β作为癫痫的潜在驱动因素。这种促炎潜力进一步反映在巨噬细胞和T细胞中显著的TNF释放和显著的凋亡，这需要进一步研究以揭示特定的信号传导途径。总之，这些数据清楚地支持了以下假设：存活的和退化的幼虫囊肿具有不同的免疫原性组分，其通过TGF-β驱动的机制调节先天免疫细胞（小胶质细胞、单核细胞、巨噬细胞）以指导Treg细胞的从头分化或细胞凋亡、脑炎症和最终癫痫。因此，在这个项目中，我们的目标是（1）揭示不同的机制途径和蠕虫分子参与免疫细胞凋亡;（2）确定信号的性质（表观遗传的、转录的）控制PGE 2-IL-10-Treg轴和这些Treg的表型、功能和稳定性;（3）在采用独特的脑切片培养系统的体外脑模型中鉴定凋亡诱导蠕虫分子的脑炎症和癫痫样潜能。该提案的最终目标是将这些发现转化为人类研究，并支持识别仍迫切需要支持适当抗炎治疗方法的症状性疾病的寄生虫生物标志物和关键免疫决定因素。

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.