Grant: CIHR Fellowship

Vast quantities of dimeric immunoglobulin A (IgA) are secreted into the human gut daily. Traditionally studied for its role in pathogen clearance, recent evidence suggests IgA can also encourage colonization by beneficial bacteria. When IgA promotes colonization, it adheres microbes to gut wall mucus, protecting them from the fecal flow. When IgA discourages colonization, it cross-links microbes to form aggregates which are more susceptible to the fecal flow. The mechanism by which IgA transitions between these roles is not understood. I hypothesize that IgA's influence on microbial fitness depends on both its concentration and affinity, where low IgA binding levels help microbes adhere to mucus but are insufficient to form aggregates, whereas high binding levels induce microbial aggregation and negative effects. Working under the supervision of Kevin Foster at the University of Oxford, I will answer three questions: 1) How are IgA concentration and affinity predicted to influence IgA selection? I will develop and experimentally parameterize simulations to understand how these factors influence IgA's effects. 2) How does IgA concentration and affinity impact cell-cell and cell-mucus interactions in a synthetic model of a human gut? 3) Can we switch IgA from positive to negative selection in a mouse model? Here, I will use vaccination to induce IgA responses in mice that are either high- or low-binding to a focal Enterobacteriaceae. Part of the work (20%) will be conducted in the lab of Dr. Emma Slack, leveraging her expertise and resources in IgA-related assays. My project promises for the first time to reveal how IgA can act as both a carrot and a stick, and could lead to technologies that manipulate IgA for better health. For example, my work raises the possibility that vaccines may be used not only to remove pathogens but also to promote colonization by an administered microbial consortia.