Androgen-mediated immunosuppression impairs the effectiveness of the immune response during acute Trypanosoma cruzi infection

Despite advances in our understanding host immune responses to Trypanosoma cruzi, Chagas disease affects an estimated 7 million people globally and continues to pose a substantial public health concern. Gonadal hormones, such as testosterone (TS), are known to modulate immunity and may affect the severity of infections, including those caused by T. cruzi. In this study, we investigated the effects of testosterone on acute experimental T. cruzi infection in male Wistar Hannover rats. Animals were placed into four groups: orchiectomized (OCX), infected, testosterone supplemented, and control. Testosterone did not affect peripheral parasitemia, but it did increase the number of amastigote nests in heart tissue, reducing circulating leukocytes and neutrophils. In the liver, testosterone insufficiency was linked to increased local inflammation, including IL-6, IL-17, MPO, and NAG activity, whereas testosterone supplementation raised IL-10 levels. In the thymus, testosterone increased thymocyte death and impaired T cell development. While testosterone enhanced the frequency of CD4⁺FOXp3⁺ regulatory T cells in the spleen, androgen deprivation promoted the development of memory T cell subpopulations and the activation of macrophages and dendritic cells. Taken together, these results show that testosterone suppresses the immune system during T. cruzi infection by reducing the activation of important immune cells without directly influencing blood parasitemia. In contrast, androgen deprivation promotes a more active immune response, suggesting that the host's hormonal state plays a critical role in immune regulation during the acute phase of Chagas disease.