Investigating the Sexual Dimorphism of Disease Tolerance in Sepsis
Date
2023-12-04
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Abstract
Sepsis is a dysregulated immune response to infection, with mortality rates as high as 30%, however, there are currently no disease-modifying treatments for this disease. One of the reasons why preclinical sepsis discoveries have failed to translate into effective human therapies is that interindividual heterogeneity has historically been neglected in preclinical sepsis research, including the fundamental contributions of biological sex on disease pathogenesis and treatment response. Epidemiologic studies have observed that males have a higher incidence, severity and mortality rate than females in sepsis, however, the mechanisms underlying this bias have not yet been established. This thesis aims to examine potential underlying mediators of the sexual dimorphism within sepsis illness severity. We investigated the impact of biological sex on host defence using a well-established mouse model of sepsis induced by fecal peritonitis. We used this model to study three principal mediators of sex- based immune response differences: the gut microbiota, sex chromosomes and sex hormones. To uncover differences in these mediators we used a transgenic and germ-free mouse model. Further, we aimed to understand the sex-based influence on infection tolerance and resistance. Lastly, we completed preliminary studies on sex-based differences in infection tolerance using a tetracycline antibiotic as a potentiator of mitochondrial tolerance. This project addressed a critical gap within sepsis research and revealed biological sex differences in infection tolerance and potential therapeutic implications.
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Dobson, B. (2023). Investigating the sexual dimorphism of disease tolerance in sepsis (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.