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Principal Investigator: CRAIG ALTIER
Organization: CORNELL UNIVERSITY
Fiscal Year: 2024
Award: $390,304
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY ABSTRACT
Infections by Salmonella present a constant threat to human health in our country and throughout the world.
Yet, our progress toward controlling salmonellosis has been largely fruitless; antibiotics are rarely warranted,
and, when used, frequently fail due to resistant strains. To control this important foodborne pathogen, it is
essential to understand the means by which it colonizes and induces disease. Chemical signals of the
intestine, including those produced by both the animal host and the microbiota, can repress Salmonella
virulence by reducing its ability to invade the intestinal epithelium. We propose that this signaling defines the
fine balance between virulence and growth of the pathogen. We have found that a novel class of chemicals
produced by species of the Gammaproteobacteria, termed diffusible signal factors (DSFs), potently represses
invasion. DSFs are quorum-sensing molecules that we have found to exist in the large intestine of mice in
sufficient concentration to inhibit Salmonella invasion. They therefore represent both a novel instance of inter-
species signaling and a means by which Salmonella disease and carriage is modulated by its biological
environment. The long-term goal of this work is to identify practical means to inhibit Salmonella invasion in
humans and thus to reduce clinical and sub-clinical salmonellosis. Our objectives are to understand how
invasion-inhibiting compounds function, and to investigate their efficacy in preventing disease. Our central
hypothesis is that the resident microbiota of the large intestine produce chemical signals that repress
Salmonella invasion, and that these signals thus dictate the balance between virulence and growth. We aim to
test the specific hypotheses that: 1) Intestinal chemical signals (including both DSFs and other microbiota-
derived compounds) modulate Salmonella virulence by controlling the proportion of the pathogen population
capable of invasion to dictate disease and carriage; 2) Signaling molecules of varying structures bind within a
single binding pocket of AraC-type invasion regulators, but utilizing different binding moieties, thus dictating
activity and competition among these signals, and; 3) Signals repressive for invasion can be produced in
animals using recombinant bacteria to reduce both clinical signs of salmonellosis and intestinal colonization by
this pathogen. The work described here is significant and innovative as it has potential to identify a novel
means of pathogen control that does not rely upon antibiotics but instead targets attributes essential to
colonization and virulence.
Terms: <129X1/SvJ Mouse><Acids><Affect><Amino Acids><Animals><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Bacteria><Behavior><Binding><Biological><Cell Communication and Signaling><Cell Signaling><Chemicals><Clinical><Co-culture><Cocultivation><Coculture><Coculture Techniques><Country><DNA><DNA Binding><DNA Binding Interaction><DNA bound><Deoxyribonucleic Acid><Dimerization><Disease><Disorder><E coli><E. coli><Ectopic Expression><Environment><Equilibrium><Escherichia coli><Fatty Acids><Formates><GI colonization><Gammaproteobacteria><Gene Expression><Gene Fusion><Gene Transcription><Generalized Growth><Genes><Genetic Transcription><Goals><Growth><Health><Human><Infection><Inflammation><Intestinal><Intestines><Intracellular Communication and Signaling><Invaded><Large Intestine><Ligands><Location><Measures><Mice><Mice Mammals><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Outcome Study><Population><Position><Positioning Attribute><Process><Production><Protein Dimerization><Proteins><Public Health><RNA Expression><Recombinants><Repression><Research><Salmonella><Salmonella infections><Salmonellosis><Scheme><Siblings><Signal Induction><Signal Repression><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Structure><Testing><Tissue Growth><Transcription><Transcription Activator><Transcription Coactivator><Transcription Factor Coactivator><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Virulence><Work><aminoacid><balance><balance function><biologic><biological signal transduction><bowel><colonization resistance><computer based prediction><food born pathogen><food borne pathogen><foodborn pathogen><foodborne pathogen><gamma Proteobacteria><gastrointestinal tract colonization><gut colonization><improved><in vivo><innovate><innovation><innovative><interspecies communication><interspecies cross-talk><interspecies signaling><intestinal colonization><intestinal epithelium><large bowel><long chain fatty acid><microbial consortia><microbial flora><microbiota><microflora><mouse model><multispecies consortia><murine model><mutant><new approaches><novel><novel approaches><novel strategies><novel strategy><ontogeny><pathogen><predictive modeling><prevent><preventing><quorum sensing><resistance strain><resistant strain><response><transcription co-activator><transcriptional co-activator><γ-Proteobacteria>