Enteric bacterial pathogens profoundly impact the health and development of children, especially in developing countries. We unexpectedly discovered that polymorphisms of tnfrsf13b in mouse determine resistance to an enteric pathogen that belongs to a family of organisms that cause much of chronic enteric infection in developing countries, and to a lesser extent in developed regions. TNFRSF13B encodes the Transmembrane Activator and CAML interactor (TACI), the receptor for BAFF and APRIL, that governs differentiation of B lymphocytes into plasma cells and production of large amounts of antigen-specific immunoglobulin (Ig). We recently discovered that a highly polymorphic gene, TNFRSF13B controls susceptibility to a murine enteropathogen, C. rodentium, that models EHEC and EPEC. How tnfrsf13b alleles govern susceptibility versus resistance is incompletely understood but our preliminary work connects these properties to the control of natural IgA sequences and production. Thus, natural IgA from wild type mice induces expression of C. rodentium virulence genes whereas IgA in tnfrsf13b-mutant and -KO mice does not. What connects the common mutations, properties of IgA and IgA independent factors to susceptibility or resistance to C. rodentium is a central goal the research we propose to conduct. The research proposed will determine how tnfrsf13b missense mutations controlling distinct properties of IgA and other features of mutant mice promote resistance to C. rodentium infection, pathogenesis and transmission. We will also investigate how ?natural? IgA produced by WT animals triggers the transcription of C. rodentium virulence genes by exploring a Tn5-mutagenized library with a negatively selectable marker driven by the ler promoter. Conducting the work proposed in this application will not only advance conceptual understanding about the co-evolution of the mammalian immune system and an important class of enteric pathogens, it may also provide specific molecular targets for development of agents to prevent or reverse the devastating impact of enteropathogenic bacteria on vulnerable individuals.
The proposed research will test the impact of TNFRSF13B genomic variants in the development of resistance and immunity to enteric bacteria in a mouse model of enterohemorrhagic disease. The research will determine how the murine equivalent of a frequent TNFRSF13B damaging allele improves resistance and decreases transmission of C. rodentium and how elements of innate immunity induce C. rodentium virulence, as preliminary work indicates. The research will advance conceptual understanding about the co-evolution of the mammalian immune system and an important class of enteric pathogens and it may well provide specific molecular targets for development of much needed therapy to break the cycle of diarrhea and malnutrition in undeveloped countries.
