title: Attenuation of biopterin synthesis prevents Escherichia coli K1 invasion of brain endothelial cells and the development of meningitis in newborn mice.
abstract: Elevated levels of pterins and nitric oxide (NO) are observed in patients with septic shock and bacterial meningitis. We demonstrate that Escherichia coli K1 infection of human brain microvascular endothelial cells (HBMECs) induces the expression of guanosine triphosphate cyclohydrolase (GCH1), the rate-limiting enzyme in pterin synthesis, thereby elevating levels of biopterin. DAHP (2,4-diamino hydroxyl pyrimidine), a specific inhibitor of GCH1, prevented biopterin and NO production and invasion of E. coli K1 in HBMECs. GCH1 interaction with Ecgp96, the receptor for outer membrane protein A of E. coli K1, also increases on infection, and suppression of Ecgp96 expression prevents GCH1 activation and biopterin synthesis. Pretreatment of newborn mice with DAHP prevented the production of biopterin and the development of meningitis. These results suggest a novel role for biopterin synthesis in the pathogenesis of E. coli K1 meningitis.
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Children’s Hospital Los Angeles, California 90027, USA.
authors.forename: Muthusamy V
authors.initials: MV
authors.lastname: Shanmuganathan
authors.forename: Subramanian
authors.initials: S
authors.lastname: Krishnan
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Fu
authors.forename: Nemani V
authors.initials: NV
authors.lastname: Prasadarao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D001708:Biopterins / Q000096:biosynthesis / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000382:microbiology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000382:microbiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004926:Escherichia coli / Q000472:pathogenicity*; D005260:Female; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors; D006801:Humans; D007042:Hypoxanthines / Q000494:pharmacology / Q000627:therapeutic use; D020814:Meningitis, Escherichia coli / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism; D014774:Virulence
chemical_list: D001425:Bacterial Outer Membrane Proteins; D004791:Enzyme Inhibitors; D007042:Hypoxanthines; D011956:Receptors, Cell Surface; C078167:OMPA outer membrane proteins; D001708:Biopterins; D009569:Nitric Oxide; D006136:GTP Cyclohydrolase; C017202:2,4-diaminohypoxanthine