Abstract
Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) is critical for the pathogenesis of Escherichia coli (E. coli) K1 meningitis, a severe central nervous system infection of the neonates. However, little is known about how E. coli K1 manipulates α7 nAChR signaling. Here, through employing immortalized cell lines, animal models, and human transcriptional analysis, we showed that E. coli K1 infection triggers releasing of secreted Ly6/Plaur domain containing 1 (SLURP1), an endogenous α7 nAChR ligand. Exogenous supplement of SLURP1, combined with SLURP1 knockdown or overexpression cell lines, showed that SLURP1 is required for E. coli K1 invasion and neutrophils migrating across the blood-brain barrier (BBB). Furthermore, we found that SLURP1 is required for E. coli K1-induced α7 nAChR activation. Finally, the promoting effects of SLURP1 on the pathogenesis of E. coli K1 meningitis was significantly abolished in the α7 nAChR knockout mice. These results reveal that E. coli K1 exploits SLURP1 to activate α7 nAChR and facilitate its pathogenesis, and blocking SLURP1-α7 nAChR interaction might represent a novel therapeutic strategy for E. coli K1 meningitis.
Highlights
Despite the widespread use of antibiotics, sepsis and meningitis remain to be severe complications in premature neonates, leading to high morbidity and mortality [1,2,3]
We found E. coli K1 infection enhanced the SLURP1 secretion in both time- and dose-dependent manner compared with uninfected human brain microvascular endothelial cells (HBMEC) (Figures 1A, B)
enzyme-linked immunosorbent assay (ELISA) showed that mice infected with E. coli K1 showed a higher concentration of SLURP1 both in the serum and cerebrospinal fluid (CSF) than that of control (Figures 1G, H)
Summary
Despite the widespread use of antibiotics, sepsis and meningitis remain to be severe complications in premature neonates, leading to high morbidity and mortality [1,2,3]. Escherichia coli K1 (E. coli K1), an opportunistic pathogen in the gut, accounts for 17.7% of meningitis patients and causes a mortality rate of 40%–58% in developing countries [4, 5]. We SLURP1 Exacerbates E. coli Meningitis found memantine, an antagonist of a7 nAChR approved by the FDA for therapy of dementia, could ameliorate E. coli K1 meningitis very efficiently [9, 10]. While these studies revealed the critical role of a7 nAChR in E. coli K1 meningitis, little is known about how E. coli K1 manipulates a7 nAChR to facilitate its translocation into the central nervous system (CNS)
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