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.