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Intranasal instillation of vesicular stomatitis virus (VSV) into mice given controllable stress (modeled by escapable foot shock, ES) resulted in enhanced pathogenicity and decreased survival relative to infected mice given uncontrollable stress (modeled by inescapable foot shock, IS) and non-shocked control mice. Survival likely reflected differential cytokine gene expression that may have been regulated by miR146a, a predicted stress-responsive upstream regulator. Controllability also enhanced the accumulation of brain T resident memory cells that persisted long after viral clearance. The unexpected facilitatory effect of ES on antiviral neuroimmune responses and pathogenicity may arise from differential immunoactivating and immunosuppressive effects of uncontrollable and controllable stress.

Vesicular stomatitis virus (VSV) applied intranasally produces a well-characterized encephalitis. However, mice that experienced controllable stress via an escapable foot-shock (ES) demonstrated an enhanced immune response relative to mice that experienced uncontrollable stress (inescapable foot shock, IS) or non-stressed control mice (NS). These differences began as early as 1 day post-infection, where IS mice show a more robust cytokine response than ES or NS mice. By 3 days post-infection, however, ES mice showed enhanced inflammatory cytokine responses in the olfactory bulb. We used the Ingenuity Pathways Analysis (IPA) platform to identify regulatory genes responsible for the differences. IPA identified miRNA146a as an upstream regulator of the antiviral response and qPCR found elevated levels (~5-fold) of miRNA146a in the olfactory bulb from ES versus IS mice. miRNA levels in the non-stressed group were below detectable limits. These results suggested increased inflammation in the brains of ES mice, which were supported by more aggressive weight loss in ES mice compared to IS or NS mice as the encephalitis progressed. By 28 days post-infection, surviving mice subjected to ES continue to show increased immune activation as evidenced by increased leukocyte infiltration and enhanced production or infiltration of CD103+ (memory phenotype) T cells relative to IS or NS mice.