Stress perception differentially regulates the inflammatory response in the CNS to a neurotropic viral pathogen

Abstract

Abstract Intranasal application of neurotropic vesicular stomatitis virus (VSV) replicates in olfactory receptor neurons and then rapidly invades the olfactory bulb (OB). VSV has an established time course of progression through discrete brain regions and of onset and recovery from encephalitis. Coincident with viral progression is a bimodal brain cytokine response composed of multiple chemokines and cytokines responsible for the prominent neuroinflammatory response. Stress can have significant, but poorly understood, effects on immune function and even less is known on how stress perception may impact immune competency. Therefore, VSV infected mice were exposed to either controllable (modeled by escapable foot shock, ES) or uncontrollable (modeled by inescapable foot shock, IS) stress prior to infection and for 1–3 days post infection (PI). OB cytokine responses were initially blunted and then amplified and dysregulated at days 1 and 3 PI, respectively. With time, dysregulated responses in ES mice were associated with increased pathogenecity. Ingenuity Pathways Analysis (IPA) identified miRNA146a as an upstream regulator of this response and qPCR found elevated OB levels (~5 fold) in ES versus IS cohorts at day 1 PI. Surprisingly, brains from mice that had long ago cleared VSV still contained an infiltrate containing CD103+ cells, a marker associated with long-term brain T resident memory cells. To our knowledge, this is the first time that stress perception has been shown to differentially modulate neuroinflammation. Our data also suggest the microRNA likely responsible for the observed stress-induced changes in the antiviral immune response to a neurotropic viral pathogen.