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. © 2012 Bongfen et al.