Quantitative analysis of mucosal IgA responses

Immune mechanisms that control bacterial infection at normally sterile systemic sites, such as the blood and secondary lymphoid organs, are well studied. In contrast we know relatively little about mechanisms controlling and eliminating bacterial infections from mucosal surfaces that are normally heavily colonized by the intestinal microbiota. Using the Salmonella diarrhea mouse model and partially attenuated S. Typhimurium strains, we have demonstrated that clearance from the gut lumen is absolutely dependent on the presence of a diverse microbiota, and that protection from re-infection requires O-antigen-specific immunoglobulin A (IgA; Endt et al., 2010; Periaswamy et al., 2012).

To circumvent problems with persistent tissue colonization and non-specific effects of elevated inflammation and niche occupancy on a re-challenge, we have developed a method to induce strong mucosal immune responses against Salmonella spp. by using a killed oral vaccine. In parallel, we have developed within-host dynamics techniques (Kaiser et al., PLoS Pathogens 2013; project 4) to quantify the process of intestinal lumen and tissue colonization. Using these, we are now establishing the mechanisms by which specific IgA and other aspects of mucosal immunity prevent reinfection. The methodology will be expanded to look for similar mechanisms controlling species of the intestinal microbiota. A deeper understanding of these issues is essential to more efficiently target vaccines and to develop appropriate tests for vaccine efficacy (Slack et al., Immunol. Rev. 2014). Furthermore, this will inform the development of immunotherapies to accompany fecal transplantation and/or microbiota engineering.