A Jak3 Mutation Protects against Cerebral Malaria Figure 7. The Jak3W81R mutation confers susceptibility to infection with different bacterial pathogens. (A) Control (C57BL/6J) and Jak3W81R homozygote mutants were infected with 56104 colony-forming units (CFUs) of Mycobacterium bovis (BCG), and 6 weeks later, mice were sacrificed and the degree of infection was assessed by determination of spleen CFUs (left) and splenomegaly (spleen index; right). (B) Jak3W81R homozygotes and B6 controls were infected by aerosol inoculation of 50 CFUs/lung of Mycobacterium tuberculosis H37Rv, and monitored for survival. (C) Jak3W81R homozygotes, Jak3W81R/+ heterozygotes and B6 controls were infected by oral gavage with 36108 CFUs of Citrobacter rodentium strain DBS100. Mice were monitored for survival for 30 days post infection. Data represent two independent experiments. doi:10.1371/journal.pone.0031012.g007 dominant negative effect of W81R could possibly act through inhibition of these early cross-phosphorylation events in heterodi- mers containing both wild type and mutant variants. Jak3 kinase activity is modulated by interaction with several proteins including JAB (Jak binding proteins), CIS, SOCS, SSI, STAM, PIAS and others [41,58]. A dominant negative effect of W81R may involve stabilization of an inhibited state following interaction of wild type and or mutant variants with these modulators. Additional biochemical studies will be required to elucidate the molecular mechanism of the W81R dominant negative effect. Finally, although the full blown T 2 /B+ SCID disease is caused by complete loss of JAK3 function in humans (homozygosity or PLoS ONE | www.plosone.org 10 February 2012 | Volume 7 | Issue 2 | e31012