Genome-Wide Mouse Mutagenesis Reveals CD45-Mediated T Cell Function as Critical in Protective Immunity to HSV-1

Herpes simplex encephalitis (hse) is a lethal neurological disease resulting from infection with herpes simplex virus 1 (hsv-1). loss-of-function mutations in the unc93b1,tlr3,trif,traf3,and tbk1 genes have been associated with a human genetic predisposition to hse,demonstrating the unc93b-tlr3-type i ifn pathway as critical in protective immunity to hsv-1. however,the tlr3,unc93b1,and trif mutations exhibit incomplete penetrance and represent only a minority of hse cases,perhaps reflecting the effects of additional host genetic factors. in order to identify new host genes,proteins and signaling pathways involved in hsv-1 and hse susceptibility,we have implemented the first genome-wide mutagenesis screen in an in vivo hsv-1 infectious model. one pedigree (named p43) segregated a susceptible trait with a fully penetrant phenotype. genetic mapping and whole exome sequencing led to the identification of the causative nonsense mutation l3x in the receptor-type tyrosine-protein phosphatase c gene (ptprcl3x),which encodes for the tyrosine phosphatase cd45. expression of mcp1,il-6,mmp3,mmp8,and the icp4 viral gene were significantly increased in the brain stems of infected ptprcl3x mice accounting for hyper-inflammation and pathological damages caused by viral replication. ptprcl3x mutation drastically affects the early stages of thymocytes development but also the final stage of b cell maturation. transfer of total splenocytes from heterozygous littermates into ptprcl3x mice resulted in a complete hsv-1 protective effect. furthermore,t cells were the only cell population to fully restore resistance to hsv-1 in the mutants,an effect that required both the cd4+ and cd8+ t cells and could be attributed to function of cd4+ t helper 1 (th1) cells in cd8+ t cell recruitment to the site of infection. altogether,these results revealed the cd45-mediated t cell function as potentially critical for infection and viral spread to the brain,and also for subsequent hse development. © 2013 caignard et al.