Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (M. tuberculosis), is responsible for more than 1.8 million deaths worldwide. Males are affected roughly twice as much as females by TB, both in terms of cases and deaths. It is tempting to speculate that such discrepancy between male and female susceptibility to TB relies at least in part on specific biological features. Indeed, sex differences are frequently observed in many infectious and non-infectious diseases and rely on biological, particularly immunological differences. The objective of our project is to explore the role and mechanisms of action of sex hormones in resistance vs. sensitivity to TB. To this end, we have assembled a consortium formed by the group of O. Neyrolles, (Partner 1, IPBS, Toulouse) specialist in immunity to TB, JC Guéry (Partner 2, CPTP, Toulouse) specialist in the action of steroid hormones on immunity and the group of L Balboa (Partner 3, non-eligible for funding, Buenos-Aires, part of an international laboratory with Partner 1) who provides access to samples from human TB patients. Beside its novelty, the strengths of our project are several: i) it will be developed both in humans, in which the differential sensitivity of males and females is well established but through unknown mechanisms, and in mice, in which the mechanisms of action of steroids on the immune response is the focus of intense investigation in general but not in the context of TB; ii) the models and genetic tools required for exploring the role of sexual hormones are already available in Partner 2 laboratory and can be easily adapted to the study of TB, thus securing the project’s feasibility. Based on previous work and our preliminary data, the project will address the following two questions: 1) What are the molecular mechanisms at work to explain sex differences in immune cells upon Mycobacterium tuberculosis infection? 2)To what extent the mechanisms identified for sex differences observed in mice apply to humans? These questions will be answered through experiments performed along three work packages. For WP1, we will use an unbiased approach to investigate the impact of sex and sex hormones on TB. Male and female mice either sensitive or resistant to TB will be infected with M. tuberculosis and we will analyze bacterial loads, histological and immunological parameters. To directly explore the role of steroids, those mice will be castrated and compared to sham-operated ones. Finally, we will restrict the expression of steroid receptors to the hematopoietic compartments using already available mice and generation of speed congenic when necessary. For WP2, we will employ existing murine models (already present in our laboratory or commercially available) on the C57BL/6 background, which display selective ablation of steroid receptors on chosen cellular compartments. Based on the literature on TB and our preliminar results we hypothesize that the following cell compartments will be key to analyze: 1) macrophages/dendritic cells, 2) T cells and, 3) innate-lymphoid cells. Here too, we will analyze bacterial loads, histological and immunological parameters after infection with M. tuberculosis. For, WP #3, we will study the impact of gender in immunity to TB in humans in two ways. First, we will have access to pleural fluid and blood samples from TB patients (and blood samples from healthy controls); second, we will analyze an in vitro assay measuring the formation of a structure induced M. tuberculosis, i.e. the granuloma using blood cells and will use of variables: the gender of blood donor, the addition of steroid or steroid receptor antagonists with the aim to measure the impact of gender/steroid on the formation of this important structure. Altogether, our project will provide knowledge on how steroid hormones impact anti-TB immunity and tissue damages and could find development beyond TB.