17β-Estradiol Is Involved in the Sexual Dimorphism of the Immune Response to Malaria

Abstract

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.

Tamoxifen Suppresses the Immune Response to Plasmodium berghei ANKA and Exacerbates Symptomatology

“…The interaction of oestrogens with their receptors activates different signalling pathways that modulate the expression of immune response genes [32]. We recently showed that parasitaemia of Plasmodium berghei ANKA-infected mice varies depending on 17βoestradiol concentration [20]. In this work, we found that tamoxifen, an estrogen receptor binding antagonist, increased parasitaemia.…”

“…In addition, 17β-oestradiol administration to intact female mice infected with P. berghei ANKA increases parasitaemia and decreases body weight. By contrast, reconstitution of gonadectomised female mice using 17β-oestradiol reduces parasitaemia and affects the immune response [19,20].…”

Testosterone induces sexual dimorphism during infection with Plasmodium berghei ANKA

“…It exhibits a marked sexual dimorphism, with males showing higher parasitaemia, symptom severity and mortality than females. Sex hormones are involved in the sexual dimorphism of the immune response in malaria ( Lopes et al., 2016 ; Legorreta-Herrera et al., 2018 ; Cervantes-Candelas et al., 2021 ); oestrogens induce immunocompetence. In contrast, testosterone, the primary male hormone, generates immunosuppression ( Wichmann et al., 1996 ; Wunderlich et al., 2002 ).…”

Influence of Gestational Hormones on the Bacteria-Induced Cytokine Response in Periodontitis

“…iPRs were initially described in the lymphocytes of pregnant women, while mPRs were described in T lymphocytes and are overexpressed during the luteal phase in CD8 + T lymphocytes. Differential expression of PRs may partially explain the differential activation of immune cells and differences in susceptibility to various infectious and noninfectious diseases between men and women [ 101 ].…”