Meningitic Escherichia coli K1 Penetration and Neutrophil Transmigration Across the Blood–Brain Barrier are Modulated by Alpha7 Nicotinic Receptor

Alpha7 nicotinic acetylcholine receptor (nAChR), an essential regulator of inflammation, is abundantly expressed in hippocampal neurons, which are vulnerable to bacterial meningitis. However, it is unknown whether α7 nAChR contributes to the regulation of these events. In this report, an aggravating role of α7 nAChR in host defense against meningitic E. coli infection was demonstrated by using α7-deficient (α7-/-) mouse brain microvascular endothelial cells (BMEC) and animal model systems. As shown in our in vitro and in vivo studies, E. coli K1 invasion and polymorphonuclear neutrophil (PMN) transmigration across the blood-brain barrier (BBB) were significantly reduced in α7-/- BMEC and α7-/- mice. Stimulation by nicotine was abolished in the α7-/- cells and animals. The same blocking effect was achieved by methyllycaconitine (α7 antagonist). The tight junction molecules occludin and ZO-1 were significantly reduced in the brain cortex of wildtype mice infected with E. coli and treated with nicotine, compared to α7-/- cells and animals. Decreased neuronal injury in the hippocampal dentate gyrus was observed in α7-/- mice with meningitis. Proinflammatory cytokines (IL-1β, IL-6, TNFα, MCP-1, MIP-1alpha, and RANTES) and adhesion molecules (CD44 and ICAM-1) were significantly reduced in the cerebrospinal fluids of the α7-/- mice with E. coli meningitis. Furthermore, α7 nAChR is the major calcium channel for nicotine- and E. coli K1-increased intracellular calcium concentrations of mouse BMEC. Taken together, our data suggest that α7 nAChR plays a detrimental role in the host defense against meningitic infection by modulation of pathogen invasion, PMN recruitment, calcium signaling and neuronal inflammation

Second hand smoke exposure and the risk of invasive meningococcal disease in children: systematic review and meta-analysis

Background Invasive meningococcal disease remains an important cause of serious morbidity and mortality in children and young people. There is a growing body of literature to suggest that exposure to passive smoke may play a role in the development of the disease, therefore we have performed a systematic review to provide a comprehensive estimate of the magnitude of this effect for smoking by any household member, by individual family members, and of maternal smoking before and after birth. Methods Four databases (Medline, Embase, PsychINFO and CAB Abstracts database) were searched to identify studies (to June 2012) and reference lists scanned for further studies. Titles, abstracts and full texts were checked for eligibility independently by two authors. Quality of included studies was assessed using the Newcastle-Ottawa Scale. Pooled odds ratios (OR) with 95% confidence intervals (CI) were estimated using random effect models, with heterogeneity quantified using I2. Results We identified 18 studies which assessed the effects of SHS on the risk of invasive meningococcal disease in children. SHS in the home doubled the risk of invasive meningococcal disease (OR 2.18, 95% CI 1.63 to 2.92, I2 = 72%), with some evidence of an exposure-response gradient. The strongest effect was seen in children under 5 years (OR 2.48, 95% CI 1.51 to 4.09, I2 = 47%). Maternal smoking significantly increased the risk of invasive meningococcal disease by 3 times during pregnancy (OR 2.93, 95% CI 1.52-5.66) and by 2 times after birth (OR 2.26, 95% CI 1.54-3.31). Conclusions SHS exposure, and particularly passive foetal exposure to maternal smoking during pregnancy, significantly increases the risk of childhood invasive meningococcal disease. It is likely that an extra 630 cases of invasive meningococcal disease annually in children under 16 are directly attributable to SHS exposure in UK homes