Grant: Project Grant

For the duration of human life outside the womb, each mucosal body site maintains a unique community of resident microbes and confines them to an external cavity or internal compartment. To accomplish this, the mucosal innate immune system must rapidly respond to imbalances and remove invaders without damaging host tissue. Secreted proteases play a central role in these responses, producing bioactive proteins/peptides when swift action is needed to combat a threat. However, if proteolytic activities are inappropriately timed or mistakenly amplified, they can cause damage to the epithelial barrier by degrading structural proteins and potentiating excessive inflammation. This, in turn, can contribute to changes in the microbial populations inhabiting mucosal surfaces, possibly triggering a sustained state of dysbiosis and disease vulnerability. This prompts the question of whether some microbiome bacteria, perhaps in a self-serving capacity, secrete proteases that dysregulate the proteolytic balance. To investigate this possibility, our project will establish a first-of-its-kind toolset for discovering novel microbiome proteases, systematically unraveling their targets, and assessing their capacity to critically compromise host defenses. The mucosal body site we have chosen for the first large-scale implementation of this toolset is the female genital tract (FGT). The proposed project integrates proteomics, metagenomics, and synthetic biology to uncover new pathways and drug targets that could one day lead to microbiome-based interventions that improve women's health.