Neuro-immune interactions at the intestinal surface

项目摘要 胃肠道(GI)是人体最大的环境界面，其免疫系统是 面临着一个独特的挑战，即在保持对饮食和微生物抗原的耐受性的同时 做好防御病原体入侵的准备。协调的抵抗和容忍机制有助于防止 病原传播，限制过度的胃肠道损害，并启动由病原体引起的恢复反应 负担或伤害。胃肠道容纳的神经元(肠相关神经元，EANS)与脊髓和 比所有其他隔室加在一起的免疫细胞还要多。Eans包括感觉神经元、中间神经元和 运动神经元，其胞体在肠内(内在)或肠外(外在)，它控制着各种 胃肠道内的功能。EAN通常是肠道病原体的靶标，导致胃肠道功能正常。 病原体清除后出现紊乱。感染后肠神经损伤的临床表现包括 未解决的低度肠炎、胃肠动力障碍和神经损伤。 然而，感染引起的神经元损伤的潜在机制还不完全。 明白了。我们最近的数据表明，小鼠肠道感染会导致iEANs的快速和持续丢失， 这与长时间的胃肠道变化有关，包括肠道运动障碍。然而，感染 历史和微生物群组成分别可以防止碘损失或加速碘恢复；研究结果 这可能有助于更好地了解人类感染后IBS和与以下相关的其他疾病 炎症过程中的损伤。影像分析显示亚型特异性神经元丢失。 沙门氏菌感染，转录学和遗传学方法表明，一种新的细胞死亡机制 依赖于炎症体途径的成分。肠道巨噬肌细胞的耗竭 (MMS)，位于肠神经元附近，以及将β2-AR靶向于髓系细胞，导致 增强感染诱导的神经元丢失，表明多发性骨髓瘤组织保护计划的功能作用 在感染时诱导的。我们的观察表明，神经元-巨噬细胞相互作用在 限制感染引起的神经元损伤或加速神经元恢复，支持其意义和 这项提议的影响。我们将描述肠道感染后神经细胞死亡的机制。 不同病原体(目标1)。我们还将定义微生物区系操作如何挽救神经元死亡 感染后，可能确定特定细菌物种在这一过程中的作用(目标2)。最后，我们会 异种神经元丢失的细胞和分子免疫调控机制研究 继发感染(Aim3)。通过利用成像、细胞分选独立的转录组学、单细胞 方法和遗传获得和功能丧失的方法，这项建议的目的是表征细胞和 肠道感染后神经免疫串扰的分子组成。

Project Summary The gastrointestinal (GI) tract comprises the largest environmental interface of the body; its immune system is posed with the unique challenge of maintaining tolerance to dietary and microbial antigens while remaining poised to protect against pathogen invasion. Coordinated resistance and tolerance mechanisms serve to prevent pathogenic dissemination, limit excessive GI damage, and initiate recovery responses induced by pathogenic burden or injury. The GI tract hosts as many neurons (enteric-associated neurons, EANs) as the spinal cord and more immune cells than all other compartments together. EANs include sensory neurons, interneurons, and motor neurons with cell bodies within (intrinsic) or outside the intestine (extrinsic), which control a variety of functions within the GI tract. EANs are often targeted by enteric pathogens, resulting in functional gastrointestinal disorders post pathogen clearance. The clinical presentations of post-infectious enteric neuronal damage include unresolved low-grade intestinal inflammation, gastrointestinal motility impairment, and nerve damage. Nevertheless, the underlying mechanisms involved in infection–induced neuronal damage are incompletely understood. Our recent data indicates that murine enteric infection results in a rapid and persistent loss of iEANs, which is associated with prolonged gastrointestinal changes including intestinal dysmotility. However, infection history and microbiota composition can prevent iEAN loss or accelerate iEAN recovery, respectively; findings that may lead to a better understanding of human post-infectious IBS and additional disorders associated with EAN damage during inflammation. Imaging analyses suggested a subtype–specific neuronal loss upon Salmonella infection, and transcriptomics and genetic approaches indicated an iEAN cell death mechanism that is dependent on components of the inflammasome pathway. Depletion of intestinal muscularis macrophages (MMs), located in close proximity to enteric neurons, as well as targeting of β2-AR on myeloid cells, resulted in enhanced infection-induced neuronal loss, suggesting a functional role for a MM tissue protective program induced upon infection. Our observations suggest a functional role for neuron–macrophage interactions in limiting infection-induced neuronal damage or accelerating neuronal recovery, supporting the significance and impact of this proposal. We will characterize mechanisms underlying neuronal cell death post enteric infection with different pathogens (Aim 1). We will also to define how microbiota manipulations can rescue neuronal death post infection, possibly defining a role for specific bacterial species in this process (Aim 2). Finally, we will investigate the cellular and molecular immune mechanisms regulating neuronal loss during heterologous secondary infections (Aim3). By utilizing imaging, cell sorting–independent transcriptomics, single-cell approaches and genetic gain– and loss–of-function approaches, this proposal aims to characterize cellular and molecular components of neuro-immune crosstalk following enteric infections.