title: Adenylate cyclase and the cyclic AMP receptor protein modulate stress resistance and virulence capacity of uropathogenic Escherichia coli.
abstract: In many bacteria, the second messenger cyclic AMP (cAMP) interacts with the transcription factor cAMP receptor protein (CRP), forming active cAMP-CRP complexes that can control a multitude of cellular activities, including expanded carbon source utilization, stress response pathways, and virulence. Here, we assessed the role of cAMP-CRP as a regulator of stress resistance and virulence in uropathogenic Escherichia coli (UPEC), the principal cause of urinary tract infections worldwide. Deletion of genes encoding either CRP or CyaA, the enzyme responsible for cAMP synthesis, attenuates the ability of UPEC to colonize the bladder in a mouse infection model, dependent on intact innate host defenses. UPEC mutants lacking cAMP-CRP grow normally in the presence of glucose but are unable to utilize alternate carbon sources like amino acids, the primary nutrients available to UPEC within the urinary tract. Relative to the wild-type UPEC isolate, the cyaA and crp deletion mutants are sensitive to nitrosative stress and the superoxide generator methyl viologen but remarkably resistant to hydrogen peroxide (H(2)O(2)) and acid stress. In the mutant strains, H(2)O(2) resistance correlates with elevated catalase activity attributable in part to enhanced translation of the alternate sigma factor RpoS. Acid resistance was promoted by both RpoS-independent and RpoS-dependent mechanisms, including expression of the RpoS-regulated DNA-binding ferritin-like protein Dps. We conclude that balanced input from many cAMP-CRP-responsive elements, including RpoS, is critical to the ability of UPEC to handle the nutrient limitations and severe environmental stresses present within the mammalian urinary tract.
authors.affiliation: Division of Microbiology and Immunology, Pathology Department, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Grant T
authors.initials: GT
authors.lastname: Donovan
authors.forename: J Paul
authors.initials: JP
authors.lastname: Norton
authors.forename: Jean M
authors.initials: JM
authors.lastname: Bower
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Mulvey
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D002373:Cyclic AMP Receptor Protein / Q000235:genetics / Q000378:metabolism*; D004927:Escherichia coli Infections / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007785:Lactose / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008808:Mice, Inbred CBA; D010269:Paraquat / Q000378:metabolism; D012808:Sigma Factor / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism / Q000382:microbiology; D014552:Urinary Tract Infections / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D056689:Uropathogenic Escherichia coli / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D014774:Virulence
chemical_list: D000596:Amino Acids; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D002373:Cyclic AMP Receptor Protein; D029968:Escherichia coli Proteins; D012808:Sigma Factor; C088010:dps protein, E coli; C069567:sigma factor KatF protein, Bacteria; D013481:Superoxides; D006861:Hydrogen Peroxide; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D005947:Glucose; D007785:Lactose; D010269:Paraquat