Testosterone-induced suppression of self-healing Plasmodium chabaudi malaria: an effect not mediated by androgen receptors?

This study investigates whether androgen receptors (AR) mediate the suppressive effect of testosterone on self-healing Plasmodium chabaudi malaria. Our data show the following. (1) Female and castrated male mice of the inbred strain C57BL/10 self-heal and survive infections when challenged with 10(6) P. chabaudi-parasitized erythrocytes. However, self-healing is prevented when circulating testosterone levels are high as in intact males or in females and castrated males pretreated with 0.9 mg testosterone twice a week for 3 weeks. (2) The lethal outcome of P. chabaudi in intact males is not affected by different doses of AR blockers such as cyproterone acetate, cyproterone, flutamide and nilutamide when applied at least 3 weeks before infection and during infection. Also, these AR blockers do not impair the testosterone-induced lethal outcome of infections in testosterone-treated females and castrated males. (3) Tfm mice possessing mutant non-functional ARs and normal 'male' testosterone levels succumb to infection with P. chabaudi. However, the corresponding wild-type mice possessing functioning ARs are able to resist P. chabaudi infections at low circulating testosterone levels. (4) In contrast to testosterone, testosterone metabolites such as 5 alpha-dihydrotestosterone, 5 beta-dihydrotestosterone, androsterone and 1-dehydrotestosterone cannot suppress self-healing in castrated male B10 mice. Our data suggest that testosterone suppresses the development of protective immunity against P. chabaudi malaria, and that this immunosuppressive effect of testosterone is not primarily mediated by the classical AR response.