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Principal Investigator: Eduardo Groisman
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $521,943
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
All pathogens require proteins to cause disease. Protein abundance reflects a delicate balance
between synthesis and degradation critical for pathogenesis and antibiotic tolerance. Protein
degradation must be tightly controlled because its effects are irreversible. We aim to determine
how related bacterial species, including the human gastroenteritis- and murine typhoid-causing
Salmonella enterica serovar Typhimurium, deploy proteolysis as an essential virulence strategy.
We will investigate how the master virulence regulator PhoP controls the abundance, activity, or
specificity of all five ATP-dependent proteases: Lon, HslUV, ClpAP, ClpXP, and FtsH. We will
examine how the PhoP antagonist EIIANtr is proteolyzed in a phoP- and lon-dependent manner
and identify the role that proteolysis of PhoP and EIIANtr plays in the expression kinetics of
virulence genes when bacteria are inside macrophages. We will uncover proteins and behaviors
controlled by the poorly understood virulence-promoting protease HslUV; critically test the role
that proteolysis of gene silencer H-NS plays in expression of foreign genes; and solve the
mechanism(s) by which protease adaptors prevent protein degradation during infection. We will
identify the signals governing expression of virulence proteins CspI and IraP via their 5' leader
mRNAs and define the domain(s) of the virulence protein MgtB mediating growth in very low
Mg2+ and survival in Slc11a1+/+ macrophages. The proposed research program takes a
comprehensive approach, including technical and conceptual innovations, to reveal significant,
broadly applicable principles in bacterial physiology and pathogenesis and new therapeutic
interventions that overcome antibiotic resistance.
Terms: <ATP-Dependent Proteases><ATP-Requiring Protease><Abdominal Typhus><Achievement><Achievement Attainment><Adaptor Protein><Adaptor Protein Gene><Adaptor Signaling Protein><Adaptor Signaling Protein Gene><Adenosine Triphosphate-Dependent Proteolytic System><Amino Acid Sequence><Antibiotic Resistance><Bacteria><Bacteria KatF protein><Bacteria rpoS protein><Bacteria sigma factor 38 protein><Bacteria sigma factor KatF protein><Bacteria sigma factor S protein><Bacterial Physiology><Behavior><Biological><Body Tissues><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chaperone><Chimera><Chimera organism><Coliform Bacilli><Disease><Disorder><Disparate><E coli><E. coli><Enteral><Enteric><Enteric Bacteria><Enteric Fever><Enterobacteria><Enterobacteriaceae><Equilibrium><Escherichia coli><Esteroproteases><Gastroenteritis><Generalized Growth><Genes><Grant><Growth><Human><Infection><Intracellular Communication and Signaling><Kinetics><Knowledge><Lon Protease><Macrophage><Mediating><Messenger RNA><Metabolic Protein Degradation><Mice><Mice Mammals><Microbe><Modern Man><Molecular Chaperones><Murine><Mus><Mφ><Natural History><Non-Polyadenylated RNA><Nramp1 protein><Pasteurella pestis><Pathogenesis><Pathogenicity Factors><Peptidases><Peptide Hydrolases><Physiologic><Physiological><Play><Polymyxin B><Primary Protein Structure><Protease Gene><Protease La><Proteases><Protein Cleavage><Protein Turnover><Proteinases><Proteins><Proteolysis><Proteolytic Enzymes><RNA><RNA Gene Products><Regulatory Protein Degradation><Research><Resistance><Resistance to antibiotics><Resistant to antibiotics><Ribonucleic Acid><Role><RpoS><S enterica serovar Typhimurium><S typhimurium><S. enterica Typhimurium><S. enterica serovar Typhimurium><S. typhimurium><SLC11A1 protein><Salmonella enterica Typhimurium><Salmonella enterica serovar Typhimurium><Salmonella typhimurium><Sigma Element><Sigma Factor><Sigma Initiation Factor><Sigma Subunit><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Starvation><Stress><Testing><Tissue Growth><Tissues><Typhoid><Typhoid Fever><Virulence><Virulence Factors><Y pestis><Y. pestis><Yersinia pestis><adapter protein><antagonism><antagonist><antibiotic drug resistance><antibiotic resistant><antibiotic tolerance><balance><balance function><biologic><biological signal transduction><chimeras><design><designing><endopeptidase La><experience><experiment><experimental research><experimental study><experiments><innovate><innovation><innovative><mRNA><natural resistance-associated macrophage protein 1><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><ontogeny><pathogen><pathogenicity gene><prevent><preventing><programs><protein degradation><protein sequence><resistant><sigma(38) protein, Bacteria><sigma(S) protein, Bacteria><social role><solute carrier 11a1><solute carrier family 11-(proton-coupled divalent metal ion transporters), member 1><tolerance to antibiotics><tolerate antibiotics><virulence gene><virulent gene>