Genome-wide mouse mutagenesis reveals CD45-mediated T cell function as critical in protective immunity to HSV-1

PLoS Pathog. 2013 Sep;9(9):e1003637. doi: 10.1371/journal.ppat.1003637. Epub 2013 Sep 12.


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 (Ptprc(L3X)), 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 Ptprc(L3X) mice accounting for hyper-inflammation and pathological damages caused by viral replication. Ptprc(L3X) 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 Ptprc(L3X) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Stem / immunology
  • Brain Stem / metabolism
  • Brain Stem / pathology
  • Brain Stem / virology
  • Cells, Cultured
  • Codon, Nonsense*
  • Crosses, Genetic
  • Disease Susceptibility
  • Encephalitis, Herpes Simplex / etiology
  • Encephalitis, Herpes Simplex / genetics*
  • Female
  • Genome-Wide Association Study
  • Herpes Simplex / immunology*
  • Herpes Simplex / pathology
  • Herpes Simplex / physiopathology
  • Herpes Simplex / virology
  • Herpesvirus 1, Human / immunology*
  • Immunity, Cellular*
  • Leukocyte Common Antigens / genetics
  • Leukocyte Common Antigens / metabolism*
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mutagenesis
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / immunology
  • Neurons / metabolism
  • Neurons / pathology
  • Neurons / virology
  • Survival Analysis
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Th1 Cells / pathology
  • Th1 Cells / virology


  • Codon, Nonsense
  • Nerve Tissue Proteins
  • Leukocyte Common Antigens
  • Ptprc protein, mouse