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Principal Investigator: George A. O'Toole
Organization: DARTMOUTH COLLEGE
Fiscal Year: 2024
Award: $387,332
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract:
We study the molecular mechanisms and signaling, from environmental input to physiological
output, that control bacterial biofilm formation, a key bacterial lifestyle linked to host-microbe
interactions and infectious disease. In particular, the capability of bacteria to sense and respond
to various microenvironments, particularly during the transition from a free-swimming to a
sessile biofilm lifestyle, contributes to the establishment of chronic infections. The underlying
mechanisms are equally important for non-pathogenic bacteria that can live in commensal
relationship with their host(s). Understanding the architecture and regulation of signaling
systems that control bacterial cell adhesion and biofilm formation is critical in the development
of novel therapies and preventative interventions, while providing fundamental insight into
bacterial signaling processes. Here, we propose mechanistic studies on a broadly conserved
cell adhesion system that is crucial for biofilm formation in a variety of pathogenic and
commensal organisms. We will focus on fundamental unanswered questions concerning how
cyclic-di-GMP networks control localization of these adhesins as well as how two such adhesins
contribute to formation of biofilms. We will also enhance the impact of our studies by
investigating a newly identified, analogous signaling system in an important commensal sulfate-
reducing bacterium. The central hypothesis of this proposal is that cyclic-di-GMP signaling
via a network of ligand-responsive DGCs regulates biofilm formation across a number of
microbes of importance in pathogenic, host-associated, and environmental contexts. We
propose the following Specific Aims to test this hypothesis:
AIM 1. Test the hypothesis that small-molecule ligands are critical for regulating the localized
cdG network via receptor complexes in P. fluorescens.
AIM 2. Test the hypothesis that discrete domain structures of LapA and MapA in Pfl contribute
to their differential impacts on biofilm formation.
AIM 3. Test the hypothesis that the sulfate-reducing bacterium LapD/LapG-like system
controls localization of this intestinal bacterium’s LapA homolog.
Terms: <Adhesions><Architecture><Bacteria><Bacterial Adhesins><Bacterial Genome><Binding><Binding Site Domain><Bio-Informatics><Biochemical><Bioinformatics><Cell Adhesion><Cell Communication and Signaling><Cell Signaling><Cell surface><Cellular Adhesion><Citrates><Communicable Diseases><Complex><Conserved Sequence><Cyclicity><Cytoplasm><D vulgaris><D. vulgaris><Desulfovibrio vulgaris><Development><Dinucleoside Phosphates><Engineering / Architecture><Esteroproteases><Family><Family member><GeneHomolog><Genetic><Glycans><Homolog><Homologous Gene><Homologue><Human><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Intestinal><Intestines><Intracellular Communication and Signaling><Intracellular Second Messenger><Life Style><Lifestyle><Ligand Binding><Ligand Binding Domain><Ligands><Link><Mediating><Membrane><Microbe><Microbial Biofilms><Modern Man><Molecular><Molecular Interaction><Organism><Output><P fluorescens><P. fluorescens><Pathogenicity><Peptidases><Peptide Hydrolases><Periodicity><Periplasmic Space><Phylogenetic Analysis><Phylogenetics><Physiologic><Physiological><Polysaccharides><Preventative intervention><Process><Production><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Pseudomonas fluorescens><Receptor Protein><Regulation><Reporting><Rhythmicity><Role><Second Messenger Systems><Second Messengers><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Surface><Swimming><System><Testing><Variant><Variation><Work><adhesin><analog><bacteria pathogen><bacterial pathogen><biofilm><biofilm community><biological signal transduction><bowel><chronic infection><community microbes><developmental><diguanylate cyclase><dinucleotide><extracellular><gut microbes><gut microbial species><host microbe association><host microbe relationship><host-microbe interactions><host-microbial interactions><host-microorganism interactions><insight><intervention for prevention><intestinal microbes><living system><membrane structure><microbe pathogen><microbial community><microbial pathogen><mixed species biofilm><multi-microorganism biofilm><multispecies biofilm><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathogenic bacteria><pathogenic microbe><periplasm><persistent infection><polymicrobial biofilm><polymicrobial community><posttranscriptional><prevention intervention><preventional intervention strategy><preventive intervention><receptor><reconstitute><reconstitution><response><signal transduction second messengers><small molecule><social role><sugar><sulfate metabolizing bacteria><sulfate reducing bacteria><tool>