An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria
Cerebral malaria (CM) is a lethal neurological complication of malaria. We implemented a genome-wide screen in mutagenized mice to identify host proteins involved in CM pathogenesis and whose inhibition may be of therapeutic value. One pedigree (P48) segregated a resistance trait whose CM-protective...
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| Veröffentlicht in: | PloS one 2012-02, Vol.7 (2), p.e31012 |
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| creator | Bongfen, Silayuv E Rodrigue-Gervais, Ian-Gael Berghout, Joanne Torre, Sabrina Cingolani, Pablo Wiltshire, Sean A Leiva-Torres, Gabriel A Letourneau, Louis Sladek, Robert Blanchette, Mathieu Lathrop, Mark Behr, Marcel A Gruenheid, Samantha Vidal, Silvia M Saleh, Maya Gros, Philippe |
| description | Cerebral malaria (CM) is a lethal neurological complication of malaria. We implemented a genome-wide screen in mutagenized mice to identify host proteins involved in CM pathogenesis and whose inhibition may be of therapeutic value. One pedigree (P48) segregated a resistance trait whose CM-protective effect was fully penetrant, mapped to chromosome 8, and identified by genome sequencing as homozygosity for a mis-sense mutation (W81R) in the FERM domain of Janus-associated kinase 3 (Jak3). The causative effect of Jak3(W81R) was verified by complementation testing in Jak3(W81R/-) double heterozygotes that were fully protected against CM. Jak3(W81R) homozygotes showed defects in thymic development with depletion of CD8(+) T cell, B cell, and NK cell compartments, and defective T cell-dependent production of IFN-γ. Adoptive transfer of normal splenocytes abrogates CM resistance in Jak3(W81R) homozygotes, an effect attributed to the CD8(+) T cells. Jak3(W81R) behaves as a dominant negative variant, with significant CM resistance of Jak3(W81R/+) heterozygotes, compared to CM-susceptible Jak3(+/+) and Jak3(+/-) controls. CM resistance in Jak3(W81R/+) heterozygotes occurs in presence of normal T, B and NK cell numbers. These findings highlight the pathological role of CD8(+) T cells and Jak3-dependent IFN-γ-mediated Th1 responses in CM pathogenesis. |
| doi_str_mv | 10.1371/journal.pone.0031012 |
| format | Article |
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We implemented a genome-wide screen in mutagenized mice to identify host proteins involved in CM pathogenesis and whose inhibition may be of therapeutic value. One pedigree (P48) segregated a resistance trait whose CM-protective effect was fully penetrant, mapped to chromosome 8, and identified by genome sequencing as homozygosity for a mis-sense mutation (W81R) in the FERM domain of Janus-associated kinase 3 (Jak3). The causative effect of Jak3(W81R) was verified by complementation testing in Jak3(W81R/-) double heterozygotes that were fully protected against CM. Jak3(W81R) homozygotes showed defects in thymic development with depletion of CD8(+) T cell, B cell, and NK cell compartments, and defective T cell-dependent production of IFN-γ. Adoptive transfer of normal splenocytes abrogates CM resistance in Jak3(W81R) homozygotes, an effect attributed to the CD8(+) T cells. Jak3(W81R) behaves as a dominant negative variant, with significant CM resistance of Jak3(W81R/+) heterozygotes, compared to CM-susceptible Jak3(+/+) and Jak3(+/-) controls. CM resistance in Jak3(W81R/+) heterozygotes occurs in presence of normal T, B and NK cell numbers. These findings highlight the pathological role of CD8(+) T cells and Jak3-dependent IFN-γ-mediated Th1 responses in CM pathogenesis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0031012</identifier><identifier>PMID: 22363534</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adoptive Transfer ; Amino Acid Sequence ; Animals ; Biology ; CD8 antigen ; Chromosome 8 ; Chromosomes ; Chromosomes, Mammalian - genetics ; Citrobacter - physiology ; Complementation ; Ethyl nitrosourea ; Ethylnitrosourea ; Female ; Gene sequencing ; Genes, Dominant - genetics ; Genetic aspects ; Genetic Predisposition to Disease ; Genomes ; Genomics ; Health aspects ; Heterozygote ; Heterozygotes ; Homozygosity ; Homozygote ; Homozygotes ; Immunophenotyping ; Janus kinase 3 ; Janus Kinase 3 - chemistry ; Janus Kinase 3 - genetics ; Lymphocytes ; Lymphocytes B ; Lymphocytes T ; Malaria ; Malaria, Cerebral - enzymology ; Malaria, Cerebral - genetics ; Malaria, Cerebral - immunology ; Malaria, Cerebral - prevention & control ; Male ; Medicine ; Mice ; Mice, Neurologic Mutants ; Molecular Sequence Data ; Mutation ; Mutation - genetics ; Mycobacterium - physiology ; Mycobacterium bovis ; Natural killer cells ; Parasites ; Pathogenesis ; Pedigree ; Phenotype ; Plasmodium ; Plasmodium berghei - physiology ; Protein Structure, Tertiary ; Proteins ; Rodents ; Spleen - pathology ; Splenocytes ; Thymus ; Vector-borne diseases ; γ-Interferon</subject><ispartof>PloS one, 2012-02, Vol.7 (2), p.e31012</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Bongfen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Bongfen et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c658t-d3a0905927257049d394f24011ba53d1568355720b94a4d69eaa3b3922ec8c593</citedby><cites>FETCH-LOGICAL-c658t-d3a0905927257049d394f24011ba53d1568355720b94a4d69eaa3b3922ec8c593</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283600/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283600/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22363534$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Beier, David R.</contributor><creatorcontrib>Bongfen, Silayuv E</creatorcontrib><creatorcontrib>Rodrigue-Gervais, Ian-Gael</creatorcontrib><creatorcontrib>Berghout, Joanne</creatorcontrib><creatorcontrib>Torre, Sabrina</creatorcontrib><creatorcontrib>Cingolani, Pablo</creatorcontrib><creatorcontrib>Wiltshire, Sean A</creatorcontrib><creatorcontrib>Leiva-Torres, Gabriel A</creatorcontrib><creatorcontrib>Letourneau, Louis</creatorcontrib><creatorcontrib>Sladek, Robert</creatorcontrib><creatorcontrib>Blanchette, Mathieu</creatorcontrib><creatorcontrib>Lathrop, Mark</creatorcontrib><creatorcontrib>Behr, Marcel A</creatorcontrib><creatorcontrib>Gruenheid, Samantha</creatorcontrib><creatorcontrib>Vidal, Silvia M</creatorcontrib><creatorcontrib>Saleh, Maya</creatorcontrib><creatorcontrib>Gros, Philippe</creatorcontrib><title>An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Cerebral malaria (CM) is a lethal neurological complication of malaria. We implemented a genome-wide screen in mutagenized mice to identify host proteins involved in CM pathogenesis and whose inhibition may be of therapeutic value. One pedigree (P48) segregated a resistance trait whose CM-protective effect was fully penetrant, mapped to chromosome 8, and identified by genome sequencing as homozygosity for a mis-sense mutation (W81R) in the FERM domain of Janus-associated kinase 3 (Jak3). The causative effect of Jak3(W81R) was verified by complementation testing in Jak3(W81R/-) double heterozygotes that were fully protected against CM. Jak3(W81R) homozygotes showed defects in thymic development with depletion of CD8(+) T cell, B cell, and NK cell compartments, and defective T cell-dependent production of IFN-γ. Adoptive transfer of normal splenocytes abrogates CM resistance in Jak3(W81R) homozygotes, an effect attributed to the CD8(+) T cells. Jak3(W81R) behaves as a dominant negative variant, with significant CM resistance of Jak3(W81R/+) heterozygotes, compared to CM-susceptible Jak3(+/+) and Jak3(+/-) controls. CM resistance in Jak3(W81R/+) heterozygotes occurs in presence of normal T, B and NK cell numbers. These findings highlight the pathological role of CD8(+) T cells and Jak3-dependent IFN-γ-mediated Th1 responses in CM pathogenesis.</description><subject>Adoptive Transfer</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Biology</subject><subject>CD8 antigen</subject><subject>Chromosome 8</subject><subject>Chromosomes</subject><subject>Chromosomes, Mammalian - genetics</subject><subject>Citrobacter - physiology</subject><subject>Complementation</subject><subject>Ethyl nitrosourea</subject><subject>Ethylnitrosourea</subject><subject>Female</subject><subject>Gene sequencing</subject><subject>Genes, Dominant - genetics</subject><subject>Genetic aspects</subject><subject>Genetic Predisposition to Disease</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Health aspects</subject><subject>Heterozygote</subject><subject>Heterozygotes</subject><subject>Homozygosity</subject><subject>Homozygote</subject><subject>Homozygotes</subject><subject>Immunophenotyping</subject><subject>Janus kinase 3</subject><subject>Janus Kinase 3 - chemistry</subject><subject>Janus Kinase 3 - genetics</subject><subject>Lymphocytes</subject><subject>Lymphocytes B</subject><subject>Lymphocytes T</subject><subject>Malaria</subject><subject>Malaria, Cerebral - enzymology</subject><subject>Malaria, Cerebral - genetics</subject><subject>Malaria, Cerebral - immunology</subject><subject>Malaria, Cerebral - prevention & control</subject><subject>Male</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Neurologic Mutants</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>Mycobacterium - physiology</subject><subject>Mycobacterium bovis</subject><subject>Natural killer cells</subject><subject>Parasites</subject><subject>Pathogenesis</subject><subject>Pedigree</subject><subject>Phenotype</subject><subject>Plasmodium</subject><subject>Plasmodium berghei - physiology</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Spleen - 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genetics</topic><topic>Mycobacterium - physiology</topic><topic>Mycobacterium bovis</topic><topic>Natural killer cells</topic><topic>Parasites</topic><topic>Pathogenesis</topic><topic>Pedigree</topic><topic>Phenotype</topic><topic>Plasmodium</topic><topic>Plasmodium berghei - physiology</topic><topic>Protein Structure, Tertiary</topic><topic>Proteins</topic><topic>Rodents</topic><topic>Spleen - pathology</topic><topic>Splenocytes</topic><topic>Thymus</topic><topic>Vector-borne diseases</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bongfen, Silayuv E</creatorcontrib><creatorcontrib>Rodrigue-Gervais, Ian-Gael</creatorcontrib><creatorcontrib>Berghout, Joanne</creatorcontrib><creatorcontrib>Torre, Sabrina</creatorcontrib><creatorcontrib>Cingolani, Pablo</creatorcontrib><creatorcontrib>Wiltshire, Sean A</creatorcontrib><creatorcontrib>Leiva-Torres, Gabriel A</creatorcontrib><creatorcontrib>Letourneau, Louis</creatorcontrib><creatorcontrib>Sladek, Robert</creatorcontrib><creatorcontrib>Blanchette, Mathieu</creatorcontrib><creatorcontrib>Lathrop, Mark</creatorcontrib><creatorcontrib>Behr, Marcel A</creatorcontrib><creatorcontrib>Gruenheid, Samantha</creatorcontrib><creatorcontrib>Vidal, Silvia M</creatorcontrib><creatorcontrib>Saleh, Maya</creatorcontrib><creatorcontrib>Gros, Philippe</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Proquest Nursing & Allied Health Source</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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We implemented a genome-wide screen in mutagenized mice to identify host proteins involved in CM pathogenesis and whose inhibition may be of therapeutic value. One pedigree (P48) segregated a resistance trait whose CM-protective effect was fully penetrant, mapped to chromosome 8, and identified by genome sequencing as homozygosity for a mis-sense mutation (W81R) in the FERM domain of Janus-associated kinase 3 (Jak3). The causative effect of Jak3(W81R) was verified by complementation testing in Jak3(W81R/-) double heterozygotes that were fully protected against CM. Jak3(W81R) homozygotes showed defects in thymic development with depletion of CD8(+) T cell, B cell, and NK cell compartments, and defective T cell-dependent production of IFN-γ. Adoptive transfer of normal splenocytes abrogates CM resistance in Jak3(W81R) homozygotes, an effect attributed to the CD8(+) T cells. Jak3(W81R) behaves as a dominant negative variant, with significant CM resistance of Jak3(W81R/+) heterozygotes, compared to CM-susceptible Jak3(+/+) and Jak3(+/-) controls. CM resistance in Jak3(W81R/+) heterozygotes occurs in presence of normal T, B and NK cell numbers. These findings highlight the pathological role of CD8(+) T cells and Jak3-dependent IFN-γ-mediated Th1 responses in CM pathogenesis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22363534</pmid><doi>10.1371/journal.pone.0031012</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-02, Vol.7 (2), p.e31012 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1323854453 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adoptive Transfer Amino Acid Sequence Animals Biology CD8 antigen Chromosome 8 Chromosomes Chromosomes, Mammalian - genetics Citrobacter - physiology Complementation Ethyl nitrosourea Ethylnitrosourea Female Gene sequencing Genes, Dominant - genetics Genetic aspects Genetic Predisposition to Disease Genomes Genomics Health aspects Heterozygote Heterozygotes Homozygosity Homozygote Homozygotes Immunophenotyping Janus kinase 3 Janus Kinase 3 - chemistry Janus Kinase 3 - genetics Lymphocytes Lymphocytes B Lymphocytes T Malaria Malaria, Cerebral - enzymology Malaria, Cerebral - genetics Malaria, Cerebral - immunology Malaria, Cerebral - prevention & control Male Medicine Mice Mice, Neurologic Mutants Molecular Sequence Data Mutation Mutation - genetics Mycobacterium - physiology Mycobacterium bovis Natural killer cells Parasites Pathogenesis Pedigree Phenotype Plasmodium Plasmodium berghei - physiology Protein Structure, Tertiary Proteins Rodents Spleen - pathology Splenocytes Thymus Vector-borne diseases γ-Interferon |
| title | An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria |
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