Impacts of antibody cross-reactivity on gut community ecology and vaccine immunogenicity

Antimicrobial resistance (AMR) is a looming global threat, rendering antibiotic treatments useless, and making bacterial infections difficult to treat. With diminishing antibiotic options to control infectious outbreaks, we must develop new strategies to prevent widespread mortality. Our group develops novel vaccines to leverage the body’s natural immune responses to fight bacterial infections. To do this, it is crucial to understand how our immune systems recognize harmful bacteria (“pathogens”), and how they distinguish them from the ‘good’ gut-resident microbes which promote human health. Oral vaccines typically induce protective immune responses which recognize sugar structures on the outer membrane of harmful bacteria, promoting their elimination. However, some of these sugar structures use the same molecular building blocks as those found on the surface of beneficial bacteria. In fact, some pathogens mimic the sugar structures of beneficial microbes to evade the immune system. In turn, this may lead to inappropriate recognition of good bacteria by the immune system. I plan to combine vaccination studies in mice with molecular tools to study direct surface sugar-immune interactions, focusing on immune responses to World Health Organization AMR priority pathogens Salmonella and Shigella. I will answer fundamental questions about immune-bacterial recognition: (1) Can immune antibodies induced in response to harmful pathogens also recognize good bacteria? (2) Does this recognition impact the composition and host-beneficial functions of gut resident microbial communities? (3) Does non-specificity of bacterial immune targeting reduce vaccine-mediated protection? Outcomes will contribute to fundamental scientific knowledge of immune-bacterial interactions and provide valuable public health insights, including explaining individual variation in vaccine protectiveness. Ultimately, this work will inform the design of effective human vaccines to combat AMR.