Brun Paola, Scarpa Melania, Marchiori Chiara, Conti Jessica, Kotsafti Andromachi, Porzionato Andrea, De Caro Raffaele, Scarpa Marco, Calistri Arianna, Castagliuolo Ignazio
Department of Molecular Medicine, University of Padua, Padua, Italy.
Esophageal and Digestive Tract Surgery Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
Front Microbiol. 2018 Sep 11;9:2148. doi: 10.3389/fmicb.2018.02148. eCollection 2018.
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 (TLR2) 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 TLR2 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 TLR2 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 TLR2 mice. At the opposite, the myenteric plexuses of TLR2 mice were surrounded by a dense infiltration of HSV-1 reactive CD3CD8INFγ lymphocytes. Indeed, depletion CD3CD8 cells by means of administration of anti-CD8 monoclonal antibody reduced neuromuscular dysfunction in TLR2 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.
1型单纯疱疹病毒（HSV-1）是一种广泛存在的嗜神经病原体，可引发一系列临床表现。炎症细胞浸润是HSV-1感染的常见特征，并与神经退行性变有关。因此，天然免疫受体（如TLR2）对病毒的识别以及随后的炎症反应现在被认为是HSV-1发病机制中的关键因素。在本研究中，我们用HSV-1感染野生型（WT）和TLR2基因敲除（TLR2）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。我们的研究结果表明，在WT和TLR2小鼠的ENS中均有病毒特异性转录本，提示存在流产性复制。此外，HSV-1在肌间神经元中触发了TLR2-MyD88依赖的信号传导，并诱导了ENS的结构和功能改变。然而，与WT小鼠相比，TLR2小鼠的胃肠动力障碍不太明显。有趣的是，HSV-1导致WT小鼠而非TLR2小鼠的肌间神经节中单核细胞趋化蛋白-1（CCL2）上调和CD11b巨噬细胞募集。相反，TLR2小鼠的肌间神经丛被HSV-1反应性CD3CD8INFγ淋巴细胞密集浸润。事实上，通过给予抗CD8单克隆抗体清除CD3CD8细胞可减轻感染HSV-1的TLR2小鼠的神经肌肉功能障碍。在HSV-1感染期间，TLR2的激活介导了感染神经元中CCL2的产生并协调巨噬细胞募集。考虑到这些观察结果，阻断TLR2信号传导可为支持保护性和特异性T细胞反应以及改善病原体介导的ENS改变中的神经肌肉功能障碍提供新的治疗策略。
