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 Jak3W81R was verified by complementation testing in Jak3W81R/− double heterozygotes that were fully protected against CM. Jak3W81R 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 Jak3W81R homozygotes, an effect attributed to the CD8+ T cells. Jak3W81R behaves as a dominant negative variant, with significant CM resistance of Jak3W81R/+ heterozygotes, compared to CM-susceptible Jak3+/+ and Jak3+/− controls. CM resistance in Jak3W81R/+ 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.
Highlights
Malaria, caused by infection with members of the Plasmodium family of parasites, still remains a global health problem, with close to 250 million clinical cases and almost a million deaths occurring each year, mostly in African children [1]
Identification and characterization of a cerebral malaria resistant ENU mutant To identify genes, proteins, and cellular pathways important for the pathogenesis of cerebral malaria (CM), we screened pedigrees derived from ENU-mutagenized mice, looking for the appearance of Cerebral malaria (CM)-resistant pheno-deviant pedigrees on the otherwise CMsusceptible genetic background of C57Bl/6J (B6)
Such pedigrees are believed to segregate protective mutations fixed for homozygosity, and affecting genes that are important for CM pathogenesis including host-driven detrimental effects
Summary
Malaria, caused by infection with members of the Plasmodium family of parasites, still remains a global health problem, with close to 250 million clinical cases and almost a million deaths occurring each year, mostly in African children [1]. CM is characterized by trapping of parasitized erythrocytes in the host microvasculature including the blood brain barrier (BBB) that triggers a strong inflammatory response in situ, vascular damage and hypoxia. Clinical epidemiological studies in different geographical areas of malaria-endemicity have indicated that the onset, progression and outcome of CM involve a complex interplay between environmental factors, parasite-expressed virulence factors and host genetic factors influencing replication of the parasite or innate or acquired immunity [3,4,5]. Genetic studies in humans have pointed to a heritable component to susceptibility to CM (reviewed in [6]), while case-control association studies have suggested a complex and heterogeneous genetic component in CM, including hemoglobin variants (hemoglobinopathies), polymorphisms in cytokine genes or gene promotors, and many others (reviewed by [3,4])
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
