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

<div><p>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 <em>Jak3^W81R</em> was verified by complementation testing in <em>Jak3^W81R/−</em> double heterozygotes that were fully protected against CM. <em>Jak3^W81R</em> 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 <em>Jak3^W81R</em> homozygotes, an effect attributed to the CD8⁺ T cells. <em>Jak3^W81R</em> behaves as a dominant negative variant, with significant CM resistance of <em>Jak3^W81R/+</em> heterozygotes, compared to CM-susceptible <em>Jak3^+/+</em> and <em>Jak3^+/−</em> controls. CM resistance in <em>Jak3^W81R/+</em> 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.</p>