Understanding the impact of sex on immunity to bacterial infection – SexFection

Immune responses to infection are highly variable among different populations. We hypothesize that variability in immune pathways, between and within female and male populations, differentially impacts how immune responses arise following exposure to bacteria. Our objective is to understand how sex hormones and sex chromosomes impact responses to pathogenic bacteria by combining analyses from a well-defined 1000-person healthy donor cohort and a validated mouse UTI model, in which female and male animals are infected via the urethra. We focus on UTI as it has a distinct sex bias, high recurrence rate, and rapidly disseminating resistance to antibiotics. Additionally, we previously showed that innate immunity to UTI is starkly different between female and male mice, resulting in resolution of infection in female mice and chronic UTI in male mice, which reflects clinical observations between female and male UTI patients. To address these questions, we will measure sex steroid sex hormones and their precursors in healthy donor plasma and immune responses to uropathogen-related stimuli in standardized whole blood stimulations from the same donors. We will integrate these measurements to determine whether sex hormone levels influence the response to bacterial stimuli. To validate our findings in humans, and to uncover pathways impacted by hormones during infection, we will manipulate hormone levels and signaling in a mouse UTI model.
In addition to sex hormones, sex chromosomes may also impact immunity. We will perform quantitative trait loci analyses with existing whole genome sequencing data to understand the influence of escape of X chromosome inactivation and loss of Y chromosome on immune pathways in human samples. In parallel in mice, we will use a specific transgenic model, in which the number of X and Y chromosomes can be changed in both sexes independently of the sex of the animal, to test the role of sex chromosomes on the response to UTI. Our findings will provide fundamental understanding of how immune variability arises between the sexes in response to infection, providing a foundation for development of non-antibiotic based immunotherapeutic approaches for UTI.