AUTHOR=Nolasco-Pérez Teresita de Jesús , Cervantes-Candelas Luis Antonio , Buendía-González Fidel Orlando , Aguilar-Castro Jesús , Fernández-Rivera Omar , Salazar-Castañón Víctor Hugo , Legorreta-Herrera Martha 

TITLE=Immunomodulatory effects of testosterone and letrozole during Plasmodium berghei ANKA infection

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 13 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2023.1146356

DOI=10.3389/fcimb.2023.1146356

ISSN=2235-2988

ABSTRACT=Malaria is one of the main health problems globally. Plasmodium infection causes a pronounced sexual  dimorphism, the lethality and severity are greater in males than 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 aromatase that can transform it  into oestrogens. To avoid the interference of these hormones, we inhibited aromatase with letrozole and analysed its impact on the symptomatology  and immune response to Plasmodium berghei ANKA infection. 
We found that administering the combination of letrozole and testosterone to Pb ANKA-infected mice  increased the concentration of free testosterone and DHEA but decreased the concentration 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 is related to important immunomodulatory effects generated by free testosterone; it selectively increased CD8+ T and CD19+ B lymphocyte populations but decreased MAC-3+. Notably, it reduced IL-17 concentration and increased IL-4 and TNF-α. Finally, it increased IgG1 levels and the IgG1/IgG2a ratio. In conclusion, free testosterone  plays an important role in pathogenesis in male mice, by increasing CD8+, decreasing MAC3+ and mainly by decreasing IL-17, 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 in inflammatory processes