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

Grégory Caignard (1) , Gabriel A Leiva-Torres (1) , Michael Leney-Greene (1) , Benoit Charbonneau (1) , Anne Dumaine (1) , Nassima Fodil-Cornu (1) , Michal Pyzik (1) , André Veillette (2) , Pablo Cingolani , Jeremy Schwartzentruber (3) , Jeremy Dupaul-Chicoine (4) , Huaijian Guo (5) , Maya Saleh (4) , Marc Lathrop (3) , Mathieu Blanchette , Jacek Majewski (3) , Angela Pearson (6) , Silvia M Vidal (1)

1 Departments of Human Genetics and Medicine
2 Laboratory of Molecular Oncology [Montréal]
3 McGill University and Genome Quebec Innovation Centre
4 Departments of Biochemistry and Medicine
5 Laboratory of Molecular Oncology
6 INRS-IAF - Institut Armand Frappier

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.

Domaines: Sciences du Vivant [q-bio]; Interactions cellulaires [q-bio.CB]; Immunité adaptative

Grégory Caignard, Gabriel A Leiva-Torres, Michael Leney-Greene, Benoit Charbonneau, Anne Dumaine, et al.. Genome-wide mouse mutagenesis reveals CD45-mediated T cell function as critical in protective immunity to HSV-1.. PLoS Pathogens, 2013, 9 (9), pp.e1003637. ⟨10.1371/journal.ppat.1003637⟩. ⟨pasteur-01130346⟩