Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 26, Pages 15949-15960Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.645812
Keywords
Escherichia coli (E; coli); host-pathogen interaction; infectious disease; iron; metabolomics; siderophore; NGAL; lipocalin 2; siderocalin; urinary tract infection
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Funding
- National Institutes of Health from NIDDK [R01DK099534, P50DK064540]
- National Center for Advancing Translational Sciences [UL1TR000448]
- Longer Life Foundation
- United States Public Health Service [P41RR000954, P30DK020579, P30HL101263, P30DK056341]
- National Institutes of Health [T32GM007067-37, AI070219, U54CK000162, K12HD001459]
- Monsanto Excellence Fund Graduate Fellowship
- Barnes-Jewish Hospital Patient Safety and Quality Fellowship Program
- Career Award for Medical Scientists from the Burroughs Welcome Fund
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Background: During urinary tract infections, humans secrete the protein siderocalin to block bacterial iron uptake. Results: Human urinary pH and metabolite composition strongly affect siderocalin's antibacterial activity. Conclusion: Siderocalin uses a subset of urinary metabolites as cofactors to withhold iron from E. coli in competition with the bacterial siderophore enterobactin. Significance: Therapeutic control of urinary composition may facilitate an important innate antibacterial defense. During Escherichia coli urinary tract infections, cells in the human urinary tract release the antimicrobial protein siderocalin (SCN; also known as lipocalin 2, neutrophil gelatinase-associated lipocalin/NGAL, or 24p3). SCN can interfere with E. coli iron acquisition by sequestering ferric iron complexes with enterobactin, the conserved E. coli siderophore. Here, we find that human urinary constituents can reverse this relationship, instead making enterobactin critical for overcoming SCN-mediated growth restriction. Urinary control of SCN activity exhibits wide ranging individual differences. We used these differences to identify elevated urinary pH and aryl metabolites as key biochemical host factors controlling urinary SCN activity. These aryl metabolites are well known products of intestinal microbial metabolism. Together, these results identify an innate antibacterial immune interaction that is critically dependent upon individualistic chemical features of human urine.
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