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

作者:Bongfen Silayuv E*; Rodrigue Gervais Ian Gael; Berghout Joanne; Torre Sabrina; Cingolani Pablo; Wiltshire Sean A; Leiva Torres Gabriel A; Letourneau Louis; Sladek Robert; Blanchette Mathieu; Lathrop Mark; Behr Marcel A; Gruenheid Samantha; Vidal Silvia M; Saleh Maya; Gros Philippe
来源:PLos One, 2012, 7(2): e31012.
DOI:10.1371/journal.pone.0031012

摘要

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-gamma. 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-gamma-mediated Th1 responses in CM pathogenesis.

  • 出版日期2012-2-21