title: An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria.
abstract: 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.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Canada.
authors.forename: Silayuv E
authors.initials: SE
authors.lastname: Bongfen
authors.forename: Ian-Gael
authors.initials: IG
authors.lastname: Rodrigue-Gervais
authors.forename: Joanne
authors.initials: J
authors.lastname: Berghout
authors.forename: Sabrina
authors.initials: S
authors.lastname: Torre
authors.forename: Pablo
authors.initials: P
authors.lastname: Cingolani
authors.forename: Sean A
authors.initials: SA
authors.lastname: Wiltshire
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Leiva-Torres
authors.forename: Louis
authors.initials: L
authors.lastname: Letourneau
authors.forename: Robert
authors.initials: R
authors.lastname: Sladek
authors.forename: Mathieu
authors.initials: M
authors.lastname: Blanchette
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Behr
authors.forename: Samantha
authors.initials: S
authors.lastname: Gruenheid
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Vidal
authors.forename: Maya
authors.initials: M
authors.lastname: Saleh
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics; D002954:Citrobacter / Q000502:physiology; D005038:Ethylnitrosourea; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D016130:Immunophenotyping; D053616:Janus Kinase 3 / Q000737:chemistry / Q000235:genetics*; D016779:Malaria, Cerebral / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009161:Mycobacterium / Q000502:physiology; D010375:Pedigree; D010641:Phenotype; D010962:Plasmodium berghei / Q000502:physiology; D017434:Protein Structure, Tertiary; D013154:Spleen / Q000473:pathology
chemical_list: D053616:Janus Kinase 3; D005038:Ethylnitrosourea