Malaria is the most lethal parasitic disease worldwide; men exhibit higher mortality and more severe symptomatology than women; however, in most studies of immune response in malaria, sex is not considered a variable. Sex hormones 17β-oestradiol and testosterone are responsible for the main physiological differences between sexes. When interacting with their receptors on different immune cells, they modify the expression of genes that modulate cell proliferation, differentiation, and synthesis of cytokines. The immunosuppressive activity of testosterone is well accepted; however, its participation in the sexual dimorphism of the immune response to malaria has not been studied. In this work, we analysed whether altering the concentration of testosterone, through increasing the concentration of this hormone for exogenous administration for three weeks, or gonadectomy before infection with Plasmodium berghei ANKA affects different cells of the immune response necessary for parasite clearance. We also assessed the concentration of pro-and anti-inflammatory cytokines in male and female CBA/Ca mice infected or not with the parasite. Our results show that testosterone changes affect females more than males, resulting in sex-associated patterns. Testosterone administration increased parasitaemia in intact males while reducing it in intact females leading to a dimorphic pattern. In addition, gonadectomy increased parasitaemia in both sexes. Moreover, testosterone administration prevented both weight loss caused by the infection in females and hypothermia in gonadectomized mice of both sexes. Boosting testosterone concentration increased CD3+ and CD8+ populations but decreased the B220+ cells exclusively in females. Additionally, testosterone reduced IFN-γ concentration and increased IL-6 levels only in females, while in males, testosterone increased the number of NK cells. Finally, gonadectomy decreased TNF-α concentration in both sexes. Our results demonstrate that testosterone induces different patterns depending on sex and testosterone concentration. The results of this work contribute to understanding the impact of modifying testosterone concentration on the immune response specific against Plasmodium and the participation of this hormone in sexual dimorphism in malaria.
Malaria is the leading cause of parasitic infection-related death globally. Additionally, malaria-associated mortality is higher in men than in women, and this sexual dimorphism reflects differences in innate and adaptive immune responses that are influenced by sex hormones. Normally, females develop more robust immune responses against parasites than males. However, most clinical and laboratory studies related to the immune response to malaria do not consider sex as a variable, and relatively few studies have compared the sex-dependent role of 17β-estradiol in this process. In this study, we decreased in vivo the levels of 17β-estradiol by gonadectomy or administered 17β-estradiol to intact or gonadectomized male and female CBA/Ca mice infected with Plasmodium berghei ANKA. Subsequently, we assessed the effects of 17β-estradiol on parasite load; the percentages of different immune cells in the spleen; the plasma levels of antibodies and pro- and anti-inflammatory cytokines; and the mRNA expression levels of cytokine-encoding genes in the brain. The results showed that the administration of 17β-estradiol increased parasitemia and decreased body weight in intact female mice. Moreover, intact females exhibited higher levels of CD8+ T cells and lower levels of NK1.1+ cells than their male counterparts under the same condition. Gonadectomy increased IFN-γ and decreased TNF-α concentrations only in intact female mice. Additionally, IL-10 levels were higher in intact females than in their male counterparts. Finally, the mRNA expression levels of cytokines coding genes in the brain showed a dimorphic pattern, i.e., gonadectomy upregulated Tnf, Il1b, and Il10 expression in males but not in females. Our findings explain the sexual dimorphism in the immune response to malaria, at least in part, and suggest potential sex-dependent implications for the efficacy of vaccines or drugs targeting malaria.
IntroductionMalaria is one of the leading health problems globally. Plasmodium infection causes pronounced sexual dimorphism, and the lethality and severity are more remarkable in males than in females. To study the role of testosterone in the susceptibility and mortality of males in malaria, it is common to increase its concentration. However, this strategy does not consider the enzyme CYP19A1 aromatase, which can transform it into oestrogens.MethodsTo avoid the interference of oestrogens, we inhibited in vivo CYP19A1 aromatase with letrozole and increased the testosterone level by exogen administration before infection with Plasmodium berghei ANKA. We measured the impact on free testosterone, 17β-oestradiol and dehydroepiandrosterone levels in plasma; additionally, we evaluated parasitaemia, body temperature, body mass, glucose levels and haemoglobin concentration. Furthermore, we evaluated the effects of testosterone on the immune response; we quantified the CD3+/CD4+, CD3+/CD8+, CD19+, Mac-3+ and NK cells in the spleen and the plasma concentrations of the cytokines IL-2, IL-4, IL-6, IFN-, IL-10, TNF-α and IL-17A. Finally, we quantified the levels of antibodies.ResultsWe found that mice treated with the combination of letrozole and testosterone and infected with Plasmodium berghei ANKA had increased concentrations of free testosterone and DHEA but decreased levels of 17β-oestradiol. As a result, parasitaemia increased, leading to severe anaemia. Interestingly, testosterone increased temperature and decreased glucose concentration as a possible testosterone-mediated regulatory mechanism. The severity of symptomatology was related to critical immunomodulatory effects generated by free testosterone; it selectively increased CD3+CD8+ T and CD19+ cells but decreased Mac-3+. Remarkably, it reduced IL-17A concentration and increased IL-4 and TNF-α. Finally, it increased IgG1 levels and the IgG1/IgG2a ratio. In conclusion, free testosterone plays an essential role in pathogenesis in male mice by increasing CD8+ and decreasing Mac3+ cells and mainly reducing IL-17A levels, which is critical in the development of anaemia. Our results are important for understanding the mechanisms that regulate the exacerbated inflammatory response in infectious diseases and would be useful for the future development of alternative therapies to reduce the mortality generated by inflammatory processes.
Malaria is the most lethal parasitic disease worldwide; the severity of symptoms and mortality are higher in men than in women, exhibiting an evident sexual dimorphism in the immune response; therefore, the contribution of 17β-estradiol and testosterone to this phenomenon has been studied. Both hormones differentially affect several aspects of innate and adaptive immunity. Dehydroepiandrosterone (DHEA) is the precursor of both hormones and is the sexual steroid in higher concentrations in humans, with immunomodulatory properties in different parasitic diseases; however, the involvement of DHEA in this sexual dimorphism has not been studied. In the case of malaria, the only information is that higher levels of DHEA are associated with reduced Plasmodium falciparum parasitemia. Therefore, this work aims to analyze the DHEA contribution to the sexual dimorphism of the immune response in malaria. We assessed the effect of modifying the concentration of DHEA on parasitemia, the number of immune cells in the spleen, cytokines, and antibody levels in plasma of CBA/Ca mice infected with Plasmodium berghei ANKA (P. berghei ANKA). DHEA differentially affected the immune response in males and females: it decreased IFN-γ, IL-2 and IL-4 concentrations only in females, whereas in gonadectomized males, it increased IgG2a and IgG3 antibodies. The results presented here show that DHEA modulates the immune response against Plasmodium differently in each sex, which helps to explain the sexual dimorphism present in malaria.
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