Sex-specific responses of myeloid cells to infectious challenges

• Applicants: Professorin Dr. Hannelore Lotter; Dr. Bianca Schneider
• Subject Area: Immunology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429191104

Infections with the protozoan parasite Entamoeba histolytica (Ehis) or the facultative intracellular bacterium Mycobacterium tuberculosis (Mtb) are more common in adult men than in women. In the murine model of hepatic amoebiasis, classical monocytes, resident macrophages, and neutrophils have been found to collectively contribute to liver damage after parasite invasion. This contribution is mediated through the production of high amounts of pro-inflammatory mediators such as TNF or chemokines involved in the recruitment of these immune cells. Previously, in studies involving mice as well as experiments conducted with human cells, we successfully illustrated that testosterone, typically associated with suppression of immune responses, significantly contributes to the production of pro-inflammatory mediators in monocytes. Monocytes also seem to play a role in the sex-specific disparity in lung pathology during Mtb infection. In both the peripheral circulation and lung tissue, the presence of monocytes is notably higher in males compared to females in the animal model of the disease. Moreover, upon infiltration of lung tissue, monocytes demonstrate increased expression of specific inflammatory markers, implying their participation in immunopathological processes similar to those observed in amoebiasis. Single-cell analysis in monocytes from transgender men undergoing testosterone-based gender-affirming hormone therapy (GAHT) confirmed that testosterone heightens their pro-inflammatory state. Intriguingly, in parallel we observed an increase in aconitate decarboxylase 1 (ACOD1), a key immunometabolism regulator, suggesting the induction of a testosterone-mediated mechanism counteracting this pro-inflammatory state. In the upcoming funding period, our focus will be on conducting a thorough analysis of the interplay between sex hormones and immunometabolism, specifically examining the immune response of myeloid cells, particularly monocytes. To achieve these objectives, we will use two murine infection models (Ehis and Mtb) reflecting the same sex difference as observed in humans along with appropriate knock-out mouse strains. In addition, we will incorporate samples from transgender individuals enrolled in the Hamburg Transgender Cohorts. Lastly, we will leverage a newly developed in vitro model of human Mtb infection and a cohort of TB patients for comprehensive immune analysis, focusing on sex disparities in Mtb and emphasising immune-metabolic mechanisms.

• DFG Programme: Research Units
• Subproject of: FOR 5068: Sex differences in immunity