Detrimental and beneficial consequences of metabolic manipulations in the herpes simplex encephalitis (HSE) and blood brain barrier (BBB) integrity Detrimental and beneficial consequences of metabolic manipulations in the herpes simplex encephalitis (HSE) and blood brain barrier (BBB) integrity Engin Berber 1,2 Deepak Sumbria 1 Barry T. Rouse 1 1 Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA 2 Department of Virology, Faculty of Veterinary Medicine, Erciyes University, Kayseri, Turkey HSV-1 is often associated with development of stromal keratitis (SK) and angiogenesis which are inflammatory events orchestrated mainly by proinflammatory T cells. HSV-1 can also cause encephalitis where immune cells enter the brain likely by crossing the BBB. We wished to measure some metabolic events required for BBB function with the view that modulating such events might provide an approach to prevent encephalitis. BBB permeability was significantly increased in the 2DG (competitor and inhibitor of glucose) given group when compared to HSV-1 infected animals. BBB leakage was confirmed by measuring the escape from the blood vasculature of injected Evans blue dye in Balb/C mice. In mice that received 2DG, animals expressed higher BBB permeability which was demonstrated by leakage of Evans blue with extravasation study. 2DG treated mice also developed diminished Th1 but not Th17 T cells response in the brain. The trigeminal ganglions (TGs) were removed from latently HSV infected mice and cultured in-vitro. Virus reactivation occurred more rapidly in 2DG added TGs when compared to untreated TGs. Virus replication increased the expression of IL-1b and IL-23 in brain microenvironment as well as when compared to control group. IL-1b and IL-23 are also driving cytokines that responsible the Th17 development. Besides 2DG addition to Th17 in-vitro induction culture was increased the IL-17A expression in Th17 cells. Findings from this study revealed that virus induced pro-inflammatory environment which stimulated brain accumulated naïve T cells to become IL-17A expressing Th17 cell phenotype in response to 2DG treatment. Balb/C mice were given metformin to inhibit gluconeogenesis during the acute infection of HSV-1. Mice were treated with metformin reduced Th17 response in the draining lymph nodes by in-vivo and dose dependently by in-vitro induction culture. Animals treated with metformin diminished the facial lesions and failed the encephalitis. Our results indicate the expression of herpetic encephalitis depend on the permeability of BBB along with appropriate generation of inflammatory T cells.