Angiotensin II Receptor Type 1—A Novel Target for Preventing Neonatal Meningitis in Mice by Escherichia coli K1
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.
Additional Information© The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. Received 30 May 2013; accepted 13 August 2013; electronically published 16 September 2013. This work was supported by the National Institutes of Health (grants AI40567 and NS73115 to N. V. P.).
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