Deletion of LTβR augments male susceptibility to Plasmodium chabaudi

Disruption of the lymphotoxin beta receptor (LT beta R) gene has been shown to result in enhanced resistance of female mice to blood-stage Plasmodium chabaudi malaria. Here, we investigate the effect of LT beta R deletion on host defence of males. In contrast to females, male LT beta R-/- mice do not exhibit any increase in resistance. Conversely, they are even more susceptible than wild-type C57BL/6 mice, which becomes evident after lowering circulating levels of testosterone by castration, which makes C57BL/6 males resistant, whereas LT beta R-/- remain susceptible. Gene-expression analysis using cDNA arrays revealed no differences in immunological responses in spleen of malaria-resistant female and malaria-susceptible castrated male LT beta R-/- mice. In the liver, however, expression levels of plasminogen activator inhibitor PAI1, chemokine CXCL10, dual specificity phosphatase DUSP1, and hydroxysteroid-specific sulfotransferases Sult2a1/2 were decreased 6- to 85-fold in susceptible castrated male LT beta R-/- mice in comparison to resistant female LT beta R-/- mice at maximal parasitaemia, as evidenced by Northern blot analyses. The present data support our previous view that the liver is involved in the combat against malarial blood stages and that down-regulation of the genes DUSP1 and Sult2a1/2 signals dysregulation of protective liver responses, thus possibly contributing to male susceptibility of LT beta R-/- mice.