Controlling herpetic inflammatory lesions by inhibiting glucose metabolism- on the different outcome of using 2DG and metformin

Abstract

Abstract Ocular infection with herpes simplex virus-1 (HSV-1) results in a blinding immunoinflammatory lesion. Control can be achieved by inhibiting the metabolism of cells principally involved in lesion development. Inhibiting glucose metabolism with 2DG achieves this effect but if therapy is used when replicating virus is still present, herpes simplex encephalitis (HSE) is likely to ensue. We report that using metformin to inhibit glucose metabolism can also minimize herpetic ocular lesions and this occurs without the usual complication of HSE. We try to provide a mechanistic explanation for the different outcomes. We show that the innate cell response in corneal lesions was similarly diminished by both metabolic therapies, but the effects on the composition of cellular T responses differed. Thus 2DG had more inhibitory effects than metformin on CD4 Th1 T cells, the main orchestrators of corneal lesions as well as on Foxp3+ Treg, cells responsible for controlling lesions. Metformin therapy had minimal inhibitory effects on Treg such that the representation of Treg markedly increased in comparison to Th1 cells. The responses occurring in the trigeminal ganglia, the site to which HSV spreads and then sets up permanent latency, was also investigated. The nature of the inflammatory responses at the site differed in untreated and animals treated with 2DG or metformin. Thus, both therapies resulted in diminished inflammatory responses particularly the innate cell composition. The inhibitory effects of 2DG against the CD8 content of the inflammatory reaction (cells advocated as involved in containing latency and stopping virus from disseminating to the brain) was significantly greater than was the metformin therapy. Supported by grants from NIH (R21AI142862 and R01EY005093)