Therapeutic manipulation of glutamine metabolism reduce HSV-1 induced pathological lesions Authors name and their affiliations- Deepak Sumbria, Engin Berber and Barry T Rouse- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, TN, 37996, USA Engin Berber- Department of Virology, Faculty of Veterinary Medicine, Erciyes University, Turkey Abstract- Ocular infection, with herpes simplex virus can result in a vision- impairing inflammatory reaction largely orchestrated by pro-inflammatory CD4 T cells. The severity of lesions can be limited if the balance of cell types involved is changed to increase the representation of regulatory T cells and M2 mononuclear cells. This reshaping might be achieved by exploiting differences in the major metabolic pathways employed by cells with different functions. In this report we investigate if the differential requirements for glutamine by cell types can be exploited to minimize the severity of ocular inflammatory reactions. We blocked glutamine by injecting intraperitoneally low dose (0.3 mg/kg) of 6-Diazo-5-oxo-L-norleucine (DON) from 6th until day 15th post infection by HSV-1. The corneal levels of CD4 Th1, Th17 T cells, neutrophils and macrophages was reduced in the DON treated group but the frequency of Treg was increased. In the trigeminal ganglion (TG), decreased levels of CD4 Th1, neutrophils and macrophages was observed. Reduced number of CD4 Th1, Th17 T cells, neutrophils and macrophages was also evident in the drainage lymph node (DLN) and in the DLN an increase in the ratio of T regulatory (Treg) to Th1 and Th17 cells was evident. The addition of DON in cultures to induce CD4 T cell subsets in-vitro reduced the magnitude of induced Th17 responses but not Th1 cells. However, Treg induction expanded. Glutamine metabolism was also shown relevant for the maintenance of herpesvirus latency. Thus when TG from infected mice were culture in vitro, a procedure that results in reactivation from latency, inhibiting glutamine metabolism significantly delayed the reactivation process. Taken together, our result indicates that glutamine metabolism is necessary for the full expression of an antiviral inflammatory response and is also needed for the maintenance of herpes virus latency.