title: Angiotensin II receptor type 1--a novel target for preventing neonatal meningitis in mice by Escherichia coli K1.
abstract: The increasing incidence of Escherichia coli K1 meningitis due to escalating antibiotic resistance warrants alternate treatment options to prevent this deadly disease. We screened a library of small molecules from the National Institutes of Health clinical collection and identified telmisartan, an angiotensin II receptor type 1 (AT1R) blocker, as a potent inhibitor of E. coli invasion into human brain microvascular endothelial cells (HBMECs). Immunoprecipitation studies revealed that AT1R associates with endothelial cell gp96, the receptor in HBMECs for E. coli outer membrane protein A. HBMECs pretreated with telmisartan or transfected with AT1R small interfering RNA were resistant to E. coli invasion because of downregulation of protein kinase C-α phosphorylation. Administration of a soluble derivative of telmisartan to newborn mice before infection with E. coli prevented the onset of meningitis and suppressed neutrophil infiltration and glial cell migration in the brain. Therefore, telmisartan has potential as an alternate treatment option for preventing E. coli meningitis.
authors.affiliation: Division of Infectious Diseases.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Krishnan
authors.forename: Muthusamy V
authors.initials: MV
authors.lastname: Shanmuganathan
authors.forename: Douglas
authors.initials: D
authors.lastname: Behenna
authors.forename: Brian M
authors.initials: BM
authors.lastname: Stoltz
authors.forename: Nemani V
authors.initials: NV
authors.lastname: Prasadarao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000942:Antigens, Bacterial; D016667:Bacterial Capsules; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D018890:Chemoprevention / Q000379:methods; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000382:microbiology*; D004926:Escherichia coli / Q000737:chemistry / Q000145:classification / Q000502:physiology*; D006801:Humans; D020814:Meningitis, Escherichia coli / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D011135:Polysaccharides, Bacterial; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D000077333:Telmisartan
chemical_list: C544065:AGTR1 protein, human; D000942:Antigens, Bacterial; D001562:Benzimidazoles; D001565:Benzoates; D011135:Polysaccharides, Bacterial; D044140:Receptor, Angiotensin, Type 1; C036962:capsular polysaccharide K1; D000077333:Telmisartan
keywords: Angiotensin II receptor type I; Escherichia coli K1; brain; human brain endothelial cells; invasion; protein kinase C-α; small molecules
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