Deletion of LTβR augments male susceptibility to Plasmodium chabaudi

Abstract

SUMMARY Disruption of the lymphotoxin beta receptor (LTbetaR) gene has been shown to result in enhanced resistance of female mice to blood-stage Plasmodium chabaudi malaria. Here, we investigate the effect of LTbetaR deletion on host defence of males. In contrast to females, male LTbetaR(-/-) 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 LTbetaR(-/-) 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 LTbetaR(-/-) 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 LTbetaR(-/-) mice in comparison to resistant female LTbetaR(-/-) 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 LTbetaR(-/-) mice.

The LymphotoxinβReceptor Is Essential for Upregulation of IFN-Induced Guanylate-Binding Proteins and Survival afterToxoplasma gondiiInfection

“…LT β R −/− mice fail to induce IFN γ , and mGBPs are subsequently not upregulated, leading to a breakdown of the antitoxoplasma immune response. These results point towards a major role for the LT β R in an efficient immune response to T. gondii and are in accordance with other studies suggesting that the LT β R acts as an important immune regulator, not only in bacterial infection models for listeriosis or tuberculosis [ 5 , 43 , 44 ] but also in intracellular parasite infection models for malaria [ 45 , 46 ] or leishmaniasis [ 47 – 50 ]. The role of the LT β R in these disease models is quite diverse.…”

Augmented particle trapping and attenuated inflammation in the liver by protective vaccination against Plasmodium chabaudi malaria

“…These analyses confirmed suppression of Sult2a mRNA levels by blood stage malaria in BALB/c mice on days 8 and 11 p.i. (Figure 7A ) as previously shown in C57BL/6 and LTβR -/- mice [ 13 , 38 ]. Vaccination, however, increased Sult2a1 mRNA levels by approximately two- and tenfold on days 0 and 8 p.i., respectively (Figure 7A ).…”

Age-Dependent Sex Bias in Clinical Malarial Disease in Hypoendemic Regions

“…The exact mechanism of the sex hormone-linked dimorphism in murine malarial infections is not completely understood. There is evidence linking the effect of sex hormones to the functioning of the immune system—especially on the balance between pro-inflammatory and regulatory processes—and responses in the liver [4], [5], [41], [42]. Further investigations are needed to determine if indeed testosterone influences susceptibility to clinical malaria in humans.…”