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Abstract：
Herpes simplex virus type 1 (HSV-1) is a widespread neurotropic pathogen responsible for a range of clinical manifestations. Inflammatory cell infiltrate is a common feature of HSV-1 infections and has been implicated in neurodegeneration. Therefore, viral recognition by innate immune receptors (i.e., TLR2) and the subsequent inflammatory response are now deemed key players in HSV-1 pathogenesis. In this study we infected with HSV-1 the enteric nervous system (ENS) of wild-type (WT) and TLR2 knock-out (TLR2ko) mice to investigate whether and how TLR2 participates in HSV-1 induced neuromuscular dysfunction. Our findings demonstrated viral specific transcripts suggestive of abortive replication in the ENS of both WT and TLR2ko mice. Moreover, HSV-1 triggered TLR2-MyD88 depend signaling in myenteric neurons and induced structural and functional alterations of the ENS. Gastrointestinal dysmotility was, however, less pronounced in TLR2ko as compared with WT mice. Interesting, HSV-1 caused up-regulation of monocyte chemoattractant protein-1 (CCL2) and recruitment of CD11b+ macrophages in the myenteric ganglia of WT but not TLR2ko mice. At the opposite, the myenteric plexuses of TLR2ko mice were surrounded by a dense infiltration of HSV-1 reactive CD3+CD8+INFγ+ lymphocytes. Indeed, depletion CD3+CD8+ cells by means of administration of anti-CD8 monoclonal antibody reduced neuromuscular dysfunction in TLR2ko mice infected with HSV-1. During HSV-1 infection, the engagement of TLR2 mediates production of CCL2 in infected neurons and coordinates macrophage recruitment. Bearing in mind these observations, blockage of TLR2 signaling could provide novel therapeutic strategies to support protective and specific T-cell responses and to improve neuromuscular dysfunction in pathogen-mediated alterations of the ENS.
摘要：
单纯疱疹病毒1型（HSV-1）是一种广泛的嗜神经病原体，可引起一系列临床表现。炎性细胞浸润是HSV-1感染的常见特征，并与神经变性有关。因此,先天免疫受体的病毒识别(即，TLR2）和随后的炎症反应现在被认为是HSV-1发病机理的关键参与者。在这项研究中，我们用HSV-1感染野生型（WT）和TLR2敲除（TLR2ko）小鼠的肠神经系统（ENS），以研究TLR2是否以及如何参与HSV-1诱导的神经肌肉功能障碍。我们的发现证明了病毒特异性转录本提示WT和TLR2ko小鼠的ENS中的失败复制。此外，HSV-1触发的TLR2-MyD88依赖于肌间神经元的信号传导并诱导ENS的结构和功能改变。胃肠动力障碍是，然而,在TLR2ko中与WT小鼠相比不太明显。有趣,HSV-1在WT而不是TLR2ko小鼠的肌间神经节中引起单核细胞趋化蛋白-1（CCL2）的上调和CD11b巨噬细胞的募集。在对面,TLR2ko小鼠的肌间神经丛被密集的HSV-1反应性CD3+CD8+INFγ+淋巴细胞浸润包围。的确,在感染HSV-1的TLR2ko小鼠中,通过施用抗CD8单克隆抗体的方式消耗CD3+CD8+细胞减少神经肌肉功能障碍。在HSV-1感染期间，TLR2的参与介导感染神经元中CCL2的产生并协调巨噬细胞的募集。记住这些观察，阻断TLR2信号可以提供新的治疗策略来支持保护性和特异性T细胞反应,并改善病原体介导的ENS改变中的神经肌肉功能障碍。
