Pellino1 is a critical regulator of HSV-1 immunity in the skin through GPR15LG 2977

Abstract Description Infections with herpes simplex viruses (HSV) are common, painful and lifelong. Pellino1 (Peli1) is an intracellular ubiquitin ligase involved in signal transduction from TLRs and cytokine receptors. The specific role for Pellino1 in the skin remains poorly understood. Using a flank skin mouse model of HSV-1 infection with neuronal involvement we examined lesion development and immune responses as the virus emerged from axons and started to replicate in the skin. Peli1-/- mice developed 2-5 times (p < 0.01) larger lesions 2 days post emergence in the skin than wild type mice. IHC revealed more extensive spread of the virus through the epidermis in Peli1-/- mice. RNA sequencing of new 1 mm lesions (<24 hours) identified a total of 82 genes that were differentially expressed: 79 downregulated and 3 upregulated in Peli1-/- mice. Gpr15lg mRNA levels were 5-15-fold (p < 0.001) higher in infected wild type mice than Peli1-/- mice, while levels were 100-1000-folder (p < 0.001) lower in uninfected mice. GPR15LG is a ligand for the G-protein coupled receptor expressed on subsets of T cells, including CD4+ helper cells. IHC and QPCR revealed that the degree of T cell recruitment in response to viral replication was significantly (p < 0.01) lower in Peli1-/- mice. Further studies used conditional knockout mice and cell cultures to determine how Pellino1 regulates Gpr15lg expression and T cell recruitment. Our data identifies a new Pellino1-GPR15LG axis important for skin immunity against HSV. Funding Sources NIH R01AI182537; NIH R01AI178128 Topic Categories Cytokines and Chemokines and Their Receptors (CCR)