Mucosal surfaces must allow the exchange of metabolites required for life into the host and excretion/exclusion of wastes and toxins out of the host, while also maintaining a first line of defense against invasive microbes. However, mucosal inflammation, elicited to combat microbial infection, can also damage the integrity of the mucosal barrier, if not controlled. Many mucosal surfaces are in constant or transient contact with microbes, yet the molecular mechanisms governing the extent of the inflammatory response at the mucosal surface and the molecular basis of a protective adaptive mucosal response are poorly understood. This proposal will investigate these mechanisms by assembling an experienced team of investigators with diverse and complimentary expertise to investigate the mucosal immune defense mechanisms of the urinary bladder against bacterial infection. We will test the hypothesis that the integration of immune signaling pathways within the first few hours of bacterial infection, including those from the bladder epithelium, constitute a mucosal immune checkpoint that has a profound impact upon the outcome of disease and bladder mucosal remodeling. The proposed research will utilize a simple and highly tractable murine model of lower urinary tract bacterial infection to probe these immune defense pathways of the bladder mucosa during acute, chronic and recurrent infection. The experimental approaches proposed will provide critical insights in the field of mucosal immunology. These studies will investigate the role of specific innate signaling pathways (Aim 1) and cellular responses (Aim 2) early in acute infection of naive mice, and the role of adaptive changes such as chronic inflammatory cell infiltrates and IgA production in establishing sensitivity to or protection from recurrent infection (Aim 3). These investigations will reveal new details of the mechanisms of mucosal defense against bacteria, broadening the understanding of the regulation of mucosal inflammation and the signaling between mucosal epithelia and immune cells, and thus advance our understanding of chronic and recurrent infection susceptibility and protection. These insights will contribute to the development of novel vaccines and therapeutics targeting the mucosa.

Public Health Relevance

These experiments are designed to reveal new mechanisms of mucosal defense against bacteria. Such findings would advance our understanding of both protective and damaging inflammatory responses at the mucosa, potentially contributing to the design of vaccines and raising new avenues for therapeutic intervention in chronic inflammatory conditions of the mucosa.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI095542-04
Application #
8678832
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Rothermel, Annette L
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Diefenbach, Andreas; Colonna, Marco; Koyasu, Shigeo (2014) Development, differentiation, and diversity of innate lymphoid cells. Immunity 41:354-65
Cortez, Victor S; Fuchs, Anja; Cella, Marina et al. (2014) Cutting edge: Salivary gland NK cells develop independently of Nfil3 in steady-state. J Immunol 192:4487-91
Cortez, Victor S; Cervantes-Barragan, Luisa; Song, Christina et al. (2014) CRTAM controls residency of gut CD4+CD8+ T cells in the steady state and maintenance of gut CD4+ Th17 during parasitic infection. J Exp Med 211:623-33
Fuchs, Anja; Colonna, Marco (2013) Innate lymphoid cells in homeostasis, infection, chronic inflammation and tumors of the gastrointestinal tract. Curr Opin Gastroenterol 29:581-7
Schwartz, Drew J; Kalas, Vasilios; Pinkner, Jerome S et al. (2013) Positively selected FimH residues enhance virulence during urinary tract infection by altering FimH conformation. Proc Natl Acad Sci U S A 110:15530-7
Fuchs, Anja; Vermi, William; Lee, Jacob S et al. (2013) Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-?-producing cells. Immunity 38:769-81
Guiton, Pascale S; Hannan, Thomas J; Ford, Bradley et al. (2013) Enterococcus faecalis overcomes foreign body-mediated inflammation to establish urinary tract infections. Infect Immun 81:329-39
Satpathy, Ansuman T; Briseno, Carlos G; Lee, Jacob S et al. (2013) Notch2-dependent classical dendritic cells orchestrate intestinal immunity to attaching-and-effacing bacterial pathogens. Nat Immunol 14:937-48
Silverman, Jennifer A; Schreiber 4th, Henry L; Hooton, Thomas M et al. (2013) From physiology to pharmacy: developments in the pathogenesis and treatment of recurrent urinary tract infections. Curr Urol Rep 14:448-56
Hannan, Thomas J; Totsika, Makrina; Mansfield, Kylie J et al. (2012) Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiol Rev 36:616-48