Rotavirus pre-symptomatically downregulates ileum-innervating sympathetic nerves concomitant with increased intestinal transit and altered brain activity

Abstract

While diarrhea, the hallmark symptom of rotavirus infection, has been considered to occur only due to intrinsic intestinal effects, we show evidence for central control underlying the symptomology. With large-scale 3D volumetric tissue imaging a mouse model, we show that rotavirus infection disrupts the autonomic balance by downregulating the noradrenergic sympathetic nervous system in ileum, concomitant with increased intestinal transit. A most interesting observation was that nervous response from CNS occurs pre-symptomatically, an observation that bring new understanding to how virus give raise to clinical symptoms. In the CNS of infected animals, we found increased pS6 immunoreactivity in the area postrema and decreased phosphorylated STAT5-immunoreactive neurons in the bed nucleus of the stria terminalis, which are associated with autonomic control including stress response. Our observations bring new and important knowledge of how rotavirus virus infection induce gut-nerve-brain crosstalk giving raise to sickness symptoms.