| Title: |
Genome-wide mouse mutagenesis reveals CD45-mediated T cell function as critical in protective immunity to HSV-1. |
| Authors: |
Caignard, Grégory; Leiva-Torres, Gabriel A; Leney-Greene, Michael; Charbonneau, Benoit; Dumaine, Anne; Fodil-Cornu, Nassima; Pyzik, Michal; Veillette, André; Cingolani, Pablo; Schwartzentruber, Jeremy; Dupaul-Chicoine, Jeremy; Guo, Huaijian; Saleh, Maya; Lathrop, Marc; Blanchette, Mathieu; Majewski, Jacek; Pearson, Angela; Vidal, Silvia M |
| Contributors: |
Departments of Human Genetics and Medicine; McGill University = Université McGill Montréal, Canada; Laboratory of Molecular Oncology Montréal; Clinical Research Institute of Montréal; McGill University and Genome Quebec Innovation Centre; Departments of Biochemistry and Medicine; Laboratory of Molecular Oncology; Armand-Frappier Santé Biotechnologie Research Centre (INRS-AFSB); Institut National de la Recherche Scientifique Québec (INRS)-Pasteur Network (Réseau International des Instituts Pasteur); This project was conducted with support of CIHR Team grant (CTP-87520). |
| Source: |
ISSN: 1553-7366. |
| Publisher Information: |
CCSD; Public Library of Science |
| Publication Year: |
2013 |
| Collection: |
Réseau International des Instituts Pasteur, Paris: HAL-RIIP |
| Subject Terms: |
[SDV]Life Sciences [q-bio]; [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB]; [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology |
| Description: |
International audience ; 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/24068938; PUBMED: 24068938; PUBMEDCENTRAL: PMC3771889 |
| DOI: |
10.1371/journal.ppat.1003637 |
| Availability: |
https://riip.hal.science/pasteur-01130346; https://riip.hal.science/pasteur-01130346v1/document; https://riip.hal.science/pasteur-01130346v1/file/journal.ppat.1003637.pdf; https://doi.org/10.1371/journal.ppat.1003637 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.4259C30D |
| Database: |
BASE |