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Abstract：
Herpes Simplex Virus type 1 (HSV-1), a neurotropic pathogen widespread in human population, infects the enteric nervous system (ENS) in humans and rodents and causes intestinal neuromuscular dysfunction in rats. Although infiltration of inflammatory cells in the myenteric plexus and neurodegeneration of enteric nerves are common features of patients suffering from functional intestinal disorders, the proof of a pathogenic link with HSV-1 is still unsettled mainly because the underlying mechanisms are largely unknown. In this study we demonstrated that following intragastrical administration HSV-1 infects neurons within the myenteric plexus resulting in functional and structural alterations of the ENS. By infecting mice with HSV-1 replication-defective strain we revealed that gastrointestinal neuromuscular anomalies were however independent of viral replication. Indeed, enteric neurons exposed to UV-inactivated HSV-1 produced monocyte chemoattractant protein-1 (MCP-1/CCL2) to recruit activated macrophages in the longitudinal muscle myenteric plexus. Infiltrating macrophages produced reactive oxygen and nitrogen species and directly harmed enteric neurons resulting in gastrointestinal dysmotility. In HSV-1 infected mice intestinal neuromuscular dysfunctions were ameliorated by in vivo administration of (i) liposomes containing dichloromethylene bisphosphonic acid (clodronate) to deplete tissue macrophages, (ii) CCR2 chemokine receptor antagonist RS504393 to block the CCL2/CCR2 pathway, (iii) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and AR-C 102222 to quench production of nitrogen reactive species produced via iNOS. Overall these data demonstrate that HSV-1 infection makes enteric neurons recruit macrophages via production of a specific chemoattractant factor. The resulting inflammatory reaction is mandatory for intestinal dysmotility. These findings provide insights into the neuro-immune communication that occurs in the ENS following HSV-1 infection and allow recognition of an original pathophysiologic mechanism underlying gastrointestinal diseases as well as identification of novel therapeutic targets.
摘要：
单纯疱疹病毒1型（HSV-1），一种普遍存在于人群中的嗜神经病原体，感染人类和啮齿动物的肠神经系统（ENS），并导致大鼠肠神经肌肉功能障碍。尽管炎性细胞在肌间神经丛浸润和肠神经变性是功能性肠道疾病患者的共同特征，与HSV-1有致病联系的证据仍未确定,主要是因为其潜在机制在很大程度上是未知的.在这项研究中，我们证明了在胃内给药后，HSV-1会感染肌间丛内的神经元，从而导致ENS的功能和结构改变。通过用HSV-1复制缺陷菌株感染小鼠，我们发现胃肠道神经肌肉异常与病毒复制无关。的确,暴露于紫外线灭活的HSV-1的肠神经元产生单核细胞趋化蛋白1（MCP-1/CCL2），以招募纵向肌肉肌间神经丛中的活化巨噬细胞。浸润的巨噬细胞产生活性氧和氮，并直接损害肠神经元，导致胃肠动力障碍。在HSV-1感染的小鼠中，通过体内施用（i）含有二氯亚甲基双膦酸（氯膦酸盐）的脂质体以消耗组织巨噬细胞，可以改善肠神经肌肉功能障碍。(ii)CCR2趋化因子受体拮抗剂RS504393阻断CCL2/CCR2通路,(iii)Nω-硝基-L-精氨酸甲酯盐酸盐(L-NAME)和AR-C102222以淬灭通过iNOS产生的氮反应性物种的产生。总之,这些数据表明HSV-1感染通过产生特定的化学引诱因子使肠神经元募集巨噬细胞。所产生的炎症反应对于肠动力障碍是强制性的。这些发现提供了对HSV-1感染后ENS中发生的神经免疫通讯的见解，并允许识别胃肠道疾病的原始病理生理机制以及识别新的治疗靶标。
