A gut-brain-body circuit mediates immune evasion in viral infection

The gut–brain axis plays an important role in regulating antiviral immunity through multiple pathways. However, the mechanisms by which these pathways respond to viral infections remain unclear. In this study, we found that mice without TRPV1+ neurons exhibited a diminished antiviral immune response. TRPV1+ neurons in the mediodorsal thalamic nucleus (MD) enhanced antiviral immune response. In addition, the administration of a TRPV1 agonist enhanced the antiviral immune response in mice, whereas a TRPV1 inhibitor suppressed such a response. Moreover, VGLUT2+TRPV1+ neurons rather than VGAT+TRPV1+ neurons played the pivotal role in antiviral immunity. We identified the bed nucleus of the stria terminalis (BST) and the dorsomedial hypothalamic nucleus (DMH) as downstream targets of the MD. Moreover, MD–BST axis facilitated the release of substance P (SP) and calcitonin gene-related peptide (CGRP) from the brain into the cerebrospinal fluid, which then entered the bloodstream to potentiate the antiviral response in macrophages. Mechanistically, SP and CGRP enhanced the type-I interferon production via the PKA-STING and PKC-IRF3 pathways, respectively. Furthermore, viral infection triggered the production of gut microbiota–derived desthiobiotin, which reduced TRPV1 expression in the MD, thereby promoting immune evasion. Notably, the desthiobiotin inhibitor ML406 enhanced antiviral immunity and blocked immune evasion. These findings provide new insights into the mechanism by which viruses regulate the gut–brain–body axis and unveil a novel immune evasion strategy with substantial implications for developing antiviral therapies. Overall design: RNA-seq profiling of brains from wild-type (WT) mice, treated with PBS, VSV, or HSV-1 for 48 hours.

肠-脑轴（gut–brain axis）可通过多条通路调控抗病毒免疫，发挥重要作用。然而，这些通路响应病毒感染的具体机制仍不明确。本研究发现，缺失TRPV1阳性神经元的小鼠，其抗病毒免疫反应显著减弱。丘脑内侧背核（mediodorsal thalamic nucleus, MD）内的TRPV1阳性神经元可增强抗病毒免疫反应。此外，给予TRPV1受体激动剂可增强小鼠的抗病毒免疫反应，而TRPV1受体抑制剂则会抑制该免疫反应。进一步研究显示，VGLUT2阳性且TRPV1阳性的神经元，而非VGAT阳性且TRPV1阳性的神经元，在抗病毒免疫中发挥关键作用。本研究鉴定出终纹床核（bed nucleus of the stria terminalis, BST）与下丘脑背内侧核（dorsomedial hypothalamic nucleus, DMH）为MD的下游靶标。此外，MD-BST轴可促进P物质（substance P, SP）与降钙素基因相关肽（calcitonin gene-related peptide, CGRP）从脑内释放至脑脊液，随后进入血液循环，以增强巨噬细胞的抗病毒反应。从机制上来说，SP与CGRP分别通过蛋白激酶A-干扰素基因刺激因子（PKA-STING）与蛋白激酶C-干扰素调节因子3（PKC-IRF3）通路促进I型干扰素的产生。此外，病毒感染可触发肠道菌群来源的脱硫生物素的产生，该物质可降低MD内TRPV1的表达，从而促进病毒的免疫逃逸。值得注意的是，脱硫生物素抑制剂ML406可增强抗病毒免疫并阻断免疫逃逸。上述研究结果为病毒调控肠-脑-体轴的机制提供了新的见解，并揭示了一种全新的免疫逃逸策略，对开发抗病毒治疗手段具有重要意义。整体实验设计：对经PBS、水疱性口炎病毒（VSV）或单纯疱疹病毒1型（HSV-1）处理48小时的野生型（WT）小鼠脑组织进行RNA测序转录组分析。