An N-ethyl-N-nitrosourea (ENU)-induced dominant negative mutation in the JAK3 kinase protects against cerebral malaria

PLoS One. 2012;7(2):e31012. doi: 10.1371/journal.pone.0031012. Epub 2012 Feb 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Amino Acid Sequence
  • Animals
  • Chromosomes, Mammalian / genetics
  • Citrobacter / physiology
  • Ethylnitrosourea
  • Female
  • Genes, Dominant / genetics*
  • Genetic Predisposition to Disease
  • Heterozygote
  • Homozygote
  • Immunophenotyping
  • Janus Kinase 3 / chemistry
  • Janus Kinase 3 / genetics*
  • Malaria, Cerebral / enzymology*
  • Malaria, Cerebral / genetics
  • Malaria, Cerebral / immunology
  • Malaria, Cerebral / prevention & control*
  • Male
  • Mice
  • Mice, Neurologic Mutants
  • Molecular Sequence Data
  • Mutation / genetics*
  • Mycobacterium / physiology
  • Pedigree
  • Phenotype
  • Plasmodium berghei / physiology
  • Protein Structure, Tertiary
  • Spleen / pathology


  • Janus Kinase 3
  • Ethylnitrosourea