We have found that the early adaptive serum immunoglobulin response plays an important role in surviving infection with non-invasive mucosal pathogens. B cells and CD4+ T cells are required to survive infection with Citrobacter rodentium, the mouse homolog for the enteropathogenic E. coli (EPEC). Wild-type mice develop small breaks in epithelial integrity during infection, allowing C. rodentium and members of the normal flora a direct portal of entry into the host. However, immunocompetent mice develop an early and robust serum IgM response and have few colony forming units (CFU) in end organs including liver and spleen. In contrast, infection proves lethal in mice lacking B cells or CD4+ T cells. Colonic infection leads to significant polymicrobial sepsis with damage to end organs. Unlike wild-type mice, CD4-deficient animals fail to mount pathogen-specific serum IgM or IgG responses during active infection. These results implicate a critical role for the systemic adaptive immune response in surviving and eventually clearing a mucosal infection. This research plan outlines a strategy to (1) establish the protective capacity of serum immunoglobulins during active infection, (2) establish the function and location(s) where CD4+ T cells stimulate a pathogen-specific humoral response in adoptively transferred CD4-deficient mice, (3) determine the location, immunophenotype, and cytokine secretion profiles of adoptively transferred CD4+ T cells, and (4) identify T cell co-stimulatory molecules and Th cytokines important in this response. In conjunction with these aims the candidate proposes a curriculum to further training in immunology, lymphocyte biology, pathology and ethical conduct in research. The candidate has completed the core clinical training as a resident in pathology and will devote at least 75% effort towards research. This training provides a necessary step in the candidate's goal to become an independent researcher investigating questions in mucosal immunology and host-microbial cross-talk in intestinal environments.
| Bry, Lynn; Brigl, Manfred; Brenner, Michael B (2006) CD4+-T-cell effector functions and costimulatory requirements essential for surviving mucosal infection with Citrobacter rodentium. Infect Immun 74:673-81 |
