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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Veröffentlicht in:PLoS pathogens 2013-09, Vol.9 (9), p.e1003637
Hauptverfasser: 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
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container_issue 9
container_start_page e1003637
container_title PLoS pathogens
container_volume 9
creator 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
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.
doi_str_mv 10.1371/journal.ppat.1003637
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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.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1003637</identifier><identifier>PMID: 24068938</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>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</subject><ispartof>PLoS pathogens, 2013-09, Vol.9 (9), p.e1003637</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>2013 Caignard et al 2013 Caignard et al</rights><rights>2013 Caignard et al. 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 credited: Caignard G, Leiva-Torres GA, Leney-Greene M, Charbonneau B, Dumaine A, et al. (2013) Genome-Wide Mouse Mutagenesis Reveals CD45-Mediated T Cell Function as Critical in Protective Immunity to HSV-1. 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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.</description><subject>Adaptive immunology</subject><subject>Animals</subject><subject>Biology</subject><subject>Brain Stem - immunology</subject><subject>Brain Stem - metabolism</subject><subject>Brain Stem - pathology</subject><subject>Brain Stem - virology</subject><subject>Cell Behavior</subject><subject>Cells, Cultured</subject><subject>Cellular Biology</subject><subject>Codon, Nonsense</subject><subject>Crosses, Genetic</subject><subject>Disease Susceptibility</subject><subject>Encephalitis, Herpes Simplex - etiology</subject><subject>Encephalitis, Herpes Simplex - genetics</subject><subject>Female</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genome-wide association studies</subject><subject>Genome-Wide Association Study</subject><subject>Health aspects</subject><subject>Herpes Simplex - immunology</subject><subject>Herpes Simplex - pathology</subject><subject>Herpes Simplex - physiopathology</subject><subject>Herpes Simplex - virology</subject><subject>Herpes simplex virus</subject><subject>Herpesvirus 1, Human - immunology</subject><subject>Immunity, Cellular</subject><subject>Immunology</subject><subject>Infections</subject><subject>Leukocyte Common Antigens - genetics</subject><subject>Leukocyte Common Antigens - metabolism</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Medical research</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred C57BL</subject><subject>Mutagenesis</subject><subject>Mutation</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Neurons - immunology</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Neurons - virology</subject><subject>Physiological aspects</subject><subject>Rodents</subject><subject>Survival Analysis</subject><subject>T cells</subject><subject>Th1 Cells - 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24068938</pmid><doi>10.1371/journal.ppat.1003637</doi><orcidid>https://orcid.org/0000-0003-1538-9146</orcidid><orcidid>https://orcid.org/0000-0001-7021-0749</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1553-7374
ispartof PLoS pathogens, 2013-09, Vol.9 (9), p.e1003637
issn 1553-7374
1553-7366
1553-7374
language eng
recordid cdi_plos_journals_1442429346
source Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; PubMed Central Open Access
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
title Genome-wide mouse mutagenesis reveals CD45-mediated T cell function as critical in protective immunity to HSV-1
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