Department of Molecular Medicine, University of Padova, Padova, Italy.
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
Front Cell Infect Microbiol. 2018 Mar 15;8:74. doi: 10.3389/fcimb.2018.00074. eCollection 2018.
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 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.
病毒 1 型（HSV-1）是一种广泛存在于人类中的神经嗜性病原体，感染人类和啮齿动物的肠神经系统（ENS），并导致大鼠肠道神经肌肉功能障碍。尽管在患有功能性肠病的患者中，炎症细胞浸润和肠神经退行性变是共同特征，但与 HSV-1 的致病联系仍未得到证实，主要是因为其潜在机制在很大程度上尚不清楚。在这项研究中，我们证明 HSV-1 通过胃内给药感染肌间神经丛内的神经元，导致 ENS 的功能和结构改变。通过用 HSV-1 复制缺陷株感染小鼠，我们揭示了胃肠道神经肌肉异常与病毒复制无关。事实上，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）以募集在纵行肌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物种，并直接损害肠神经元，导致胃肠道动力障碍。在 HSV-1 感染的小鼠中，通过以下方式改善肠道神经肌肉功能障碍：（i）用含有二氯亚甲基双膦酸（氯膦酸盐）的脂质体处理以耗尽组织巨噬细胞，（ii）用 CCR2 趋化因子受体拮抗剂 RS504393 阻断 CCL2/CCR2 途径，（iii）用 Nω-硝基-L-精氨酸甲酯盐酸盐（L-NAME）和 AR-C 102222 抑制 iNOS 产生的氮反应性物质的产生。总的来说，这些数据表明 HSV-1 感染使肠神经元通过产生特定的趋化因子因子募集巨噬细胞。由此产生的炎症反应是肠道动力障碍的必要条件。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深入了解，并允许识别胃肠道疾病的潜在病理生理机制，并确定新的治疗靶点。
