title: THEMIS is required for pathogenesis of cerebral malaria and protection against pulmonary tuberculosis.
abstract: We identify an N-ethyl-N-nitrosourea (ENU)-induced I23N mutation in the THEMIS protein that causes protection against experimental cerebral malaria (ECM) caused by infection with Plasmodium berghei ANKA. Themis(I23N) homozygous mice show reduced CD4(+) and CD8(+) T lymphocyte numbers. ECM resistance in P. berghei ANKA-infected Themis(I23N) mice is associated with decreased cerebral cellular infiltration, retention of blood-brain barrier integrity, and reduced proinflammatory cytokine production. THEMIS(I23N) protein expression is absent from mutant mice, concurrent with the decreased THEMIS(I23N) stability observed in vitro. Biochemical studies in vitro and functional complementation in vivo in Themis(I23N/+):Lck(-/+) doubly heterozygous mice demonstrate that functional coupling of THEMIS to LCK tyrosine kinase is required for ECM pathogenesis. Damping of proinflammatory responses in Themis(I23N) mice causes susceptibility to pulmonary tuberculosis. Thus, THEMIS is required for the development and ultimately the function of proinflammatory T cells. Themis(I23N) mice can be used to study the newly discovered association of THEMIS (6p22.33) with inflammatory bowel disease and multiple sclerosis.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada Complex Traits Group, McGill University, Montreal, QC, Canada.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Torre
authors.affiliation: Department of Natural Resource Sciences, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC, Canada.
authors.forename: Sebastien P
authors.initials: SP
authors.lastname: Faucher
authors.affiliation: Complex Traits Group, McGill University, Montreal, QC, Canada Department of Biochemistry, McGill University, Montreal, QC, Canada.
authors.forename: Nassima
authors.initials: N
authors.lastname: Fodil
authors.affiliation: Complex Traits Group, McGill University, Montreal, QC, Canada Department of Biochemistry, McGill University, Montreal, QC, Canada.
authors.forename: Silayuv E
authors.initials: SE
authors.lastname: Bongfen
authors.affiliation: Complex Traits Group, McGill University, Montreal, QC, Canada Department of Biochemistry, McGill University, Montreal, QC, Canada.
authors.forename: Joanne
authors.initials: J
authors.lastname: Berghout
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada McGill and Genome Quebec Innovation Center, McGill University, Montreal, QC, Canada.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Schwartzentruber
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada McGill and Genome Quebec Innovation Center, McGill University, Montreal, QC, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada McGill and Genome Quebec Innovation Center, McGill University, Montreal, QC, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Trudeau Institute, Saranac Lake, New York, New York, USA.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Cooper
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada Complex Traits Group, McGill University, Montreal, QC, Canada Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Vidal
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada Complex Traits Group, McGill University, Montreal, QC, Canada Department of Biochemistry, McGill University, Montreal, QC, Canada philippe.gros@mcgill.ca.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002446:Celiac Disease / Q000235:genetics; D005038:Ethylnitrosourea; D015870:Gene Expression; D007249:Inflammation / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics*; D016779:Malaria, Cerebral / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018512:Parasitemia / Q000473:pathology; D010962:Plasmodium berghei / Q000276:immunology*; D011506:Proteins / Q000235:genetics* / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; C544192:themis protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D005038:Ethylnitrosourea