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


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Caignard, Gregory, Leiva-Torres, Gabriel A., Leney-Greene, Michael, Charbonneau, Benoît, 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 et Vidal, Silvia M. (2013). Genome-Wide Mouse Mutagenesis Reveals CD45-Mediated T Cell Function as Critical in Protective Immunity to HSV-1 PLoS Pathogens , vol. 9 , nº 9. e1003637. DOI: 10.1371/journal.ppat.1003637.

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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.

Type de document: Article
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 08 mars 2016 21:12
Dernière modification: 10 mai 2021 19:17
URI: https://espace.inrs.ca/id/eprint/2870

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