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.

Functional Local Renin-Angiotensin System in Human and Rat Periodontal Tissue

“…coli invasion may depend partly on the AT 1 R. Moreover, this study reported that the outer membrane receptor of E . coli can induce the formation of a protein complex involving AT 1 R and the toll-like receptor 2 (TLR2) which could mediate bacteria invasion [ 42 ]. For this reason, it is possible that some similar mechanisms occur during experimental periodontitis in vivo .…”

Pertussis Toxin Exploits Specific Host Cell Signaling Pathways for Promoting Invasion and Translocation of Escherichia coli K1 RS218 in Human Brain-derived Microvascular Endothelial Cells

“…PTx could not only up-regulate AT1R expression but also enhance AT1R-induced Ca 2ϩ influx. Interestingly, AT1R was shown to be involved in E. coli K1 RS218 invasion because inhibition of AT1R by telmisartan or siRNA-mediated knockdown abolished E. coli K1 RS218 invasion (43). Furthermore, AT1R seems to interact with gp96 and, upon binding of E. coli K1 RS218, induces Ca 2ϩ influx.…”

Host–pathogen interactions in bacterial meningitis

“…Both aminoguanidine and DAHP inhibited the onset of meningitis in 3-day-old mice by E. coli , highlighting the significance of NO production in the pathogenesis [ 79 , 121 ]. In addition, screening of a small molecule library using HBMEC invasion assays recognized Telmisartan, an angiotensin II receptor 1 (AT1R) blocker as a potent inhibitor of invasion [ 64 ]. Follow-up experiments demonstrated that AT1R forms a complex with Ecgp96 during E. coli invasion of HBMEC.…”