Abstract
Escherichia coli-induced meningitis remains a life-threatening disease despite recent advances in the field of antibiotics-based therapeutics, necessitating continued research on its pathogenesis. The current study aims to elucidate the mechanism through which hemolysin-coregulated protein 1 (Hcp1) induces the apoptosis of human brain microvascular endothelial cells (HBMEC). Co-immunoprecipitation coupled with mass spectrometric (MS) characterization led to the identification of IQ motif containing GTPase activating protein 1 (IQGAP1) as a downstream target of Hcp1. IQGAP1 was found to be up-regulated by Hcp1 treatment and mediate the stimulation of HBMEC apoptosis. It was shown that Hcp1 could compete against Smurf1 for binding to IQGAP1, thereby rescuing the latter from ubiquitin-dependent degradation. Subsequent study suggested that IQGAP1 could stimulate the MAPK signaling pathway by promoting the phosphorylation of ERK1/2, an effect that was blocked by U0126, an MAPK inhibitor. Furthermore, U0126 also demonstrated therapeutic potential against E. coli meningitis in a mouse model. Taken together, our results suggested the feasibility of targeting the MAPK pathway as a putative therapeutic strategy against bacterial meningitis.
Highlights
Bacterial meningitis is a type of inflammation caused by an infectious bacterial species in the meninges, which consist of three layers of protective membranes that surround the brain and the spinal cord (Grimwood et al, 2000)
We observed similar apoptotic levels between human brain microvascular endothelial cells (HBMEC) cells infected by wild-type RS218 and those treated with hemolysin-coregulated protein 1 (Hcp1) (Figure 1A)
When we incubated HBMEC cells with increasing concentrations of His-Hcp1, we found that the fraction of IQ motif containing GTPase activating protein 1 (IQGAP1) that was associated with Smurf1 declined in a dosedependent manner as the percentage bound to Hcp1 increased (Figure 4E)
Summary
Bacterial meningitis is a type of inflammation caused by an infectious bacterial species in the meninges, which consist of three layers of protective membranes that surround the brain and the spinal cord (Grimwood et al, 2000). Common causative agents of bacterial meningitis include Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus agalactiae, Escherichia coli, etc (Schut et al, 2008; Brouwer et al, 2010). Despite the development of vaccines and antibiotics that have provided highly effective preventative and treatment solutions, bacterial meningitis remains a dangerous disease. ∼4,100 cases of bacterial meningitis were recorded in the United States between 2003 and 2007 with a mortality rate of 12.2% (Thigpen et al, 2011). Clinical and laboratory data have demonstrated that conventional antimicrobial therapeutics often lead to less-than-satisfactory outcome in bacterial meningitis patients (Kim, 1985; Flores et al, 2013), highlighting the gaps in the current understanding of the pathogenic mechanism of the disease.
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