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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.

An N-Ethyl-N-Nitrosourea (ENU)-Induced Dominant Negative Mutation in the JAK3 Kinase Protects against Cerebral Malaria