Testosterone Regulates Sex-Dependent Immune Responses and Androgen Receptor Expression During Plasmodium berghei ANKA Infection

Malaria exhibits pronounced sexual dimorphism, with males experiencing greater disease severity and mortality than females do. Although these differences have been partially attributed to the immunosuppressive effects of testosterone, the underlying mechanisms remain poorly understood. Here, we investigated the role of testosterone in sex-specific immune responses by administering a combination of letrozole and testosterone (LT) to male and female mice infected with Plasmodium berghei ANKA. LT treatment increased testosterone concentrations in both sexes and was associated with higher parasitemia, and splenic index mainly in males, whereas hemoglobin levels decreased only in males. In females, LT increased macrophage numbers, reduced B-cell numbers, enhanced IgM production, increased androgen receptor (AR) expression, and decreased estrogen receptor-α (ERα) expression. In contrast, LT selectively reduced IL-17A levels in males without modifying AR expression. In addition, the IL-2, IFN-γ, and IL-10 levels remained unchanged in both sexes. These findings demonstrate that testosterone differentially regulates immune responses during malaria through sex-specific modulation of steroid hormone receptor expression. This study provides insight into how testosterone contributes to sex-dependent immune responses to malaria. In turn, elucidating the role of testosterone in these differences may help identify new therapeutic opportunities tailored to biological sex and ultimately contribute to the development of more effective strategies for managing infectious diseases.