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

• Published in: PLoS pathogens 2013-09, Vol.9 (9), p.e1003637
• Main Authors: Caignard, Grégory, Leiva-Torres, Gabriel A, Leney-Greene, Michael, Charbonneau, Benoit, Dumaine, Anne, Fodil-Cornu, Nassima, Pyzik, Michal, Cingolani, Pablo, Schwartzentruber, Jeremy, Dupaul-Chicoine, Jeremy, Guo, Huaijian, Saleh, Maya, Veillette, André, Lathrop, Marc, Blanchette, Mathieu, Majewski, Jacek, Pearson, Angela, Vidal, Silvia M
• Format: Article
• Language: English
• Subjects: Adaptive immunology; Animals; Biology; Brain Stem - immunology; Brain Stem - metabolism; Brain Stem - pathology; Brain Stem - virology; Cell Behavior; Cells, Cultured; Cellular Biology; Codon, Nonsense; Crosses, Genetic; Disease Susceptibility; Encephalitis, Herpes Simplex - etiology; Encephalitis, Herpes Simplex - genetics; Female; Genes; Genetic aspects; Genome-wide association studies; Genome-Wide Association Study; Health aspects; Herpes Simplex - immunology; Herpes Simplex - pathology; Herpes Simplex - physiopathology; Herpes Simplex - virology; Herpes simplex virus; Herpesvirus 1, Human - immunology; Immunity, Cellular; Immunology; Infections; Leukocyte Common Antigens - genetics; Leukocyte Common Antigens - metabolism; Life Sciences; Male; Medical research; Mice, Inbred BALB C; Mice, Inbred C57BL; Mutagenesis; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - immunology; Neurons - metabolism; Neurons - pathology; Neurons - virology; Physiological aspects; Rodents; Survival Analysis; T cells; Th1 Cells - immunology; Th1 Cells - metabolism; Th1 Cells - pathology; Th1 Cells - virology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003637

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.