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

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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771889/
https://www.ncbi.nlm.nih.gov/pubmed/24068938
http://dx.doi.org/10.1371/journal.ppat.1003637
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author 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.
author_facet 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.
author_sort Caignard, Grégory
collection PubMed
description 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.
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spelling pubmed-37718892013-09-25 Genome-Wide Mouse Mutagenesis Reveals CD45-Mediated T Cell Function as Critical in Protective Immunity to HSV-1 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. PLoS Pathog Research Article 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. Public Library of Science 2013-09-12 /pmc/articles/PMC3771889/ /pubmed/24068938 http://dx.doi.org/10.1371/journal.ppat.1003637 Text en © 2013 Caignard et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
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.
Genome-Wide Mouse Mutagenesis Reveals CD45-Mediated T Cell Function as Critical in Protective Immunity to HSV-1
title Genome-Wide Mouse Mutagenesis Reveals CD45-Mediated T Cell Function as Critical in Protective Immunity to HSV-1
title_full Genome-Wide Mouse Mutagenesis Reveals CD45-Mediated T Cell Function as Critical in Protective Immunity to HSV-1
title_fullStr Genome-Wide Mouse Mutagenesis Reveals CD45-Mediated T Cell Function as Critical in Protective Immunity to HSV-1
title_full_unstemmed Genome-Wide Mouse Mutagenesis Reveals CD45-Mediated T Cell Function as Critical in Protective Immunity to HSV-1
title_short Genome-Wide Mouse Mutagenesis Reveals CD45-Mediated T Cell Function as Critical in Protective Immunity to HSV-1
title_sort genome-wide mouse mutagenesis reveals cd45-mediated t cell function as critical in protective immunity to hsv-1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771889/
https://www.ncbi.nlm.nih.gov/pubmed/24068938
http://dx.doi.org/10.1371/journal.ppat.1003637
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