Endogenous α7 nAChR Agonist SLURP1 Facilitates Escherichia coli K1 Crossing the Blood-Brain Barrier.

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.

Escherichia Coli Meningitis Features in 325 Children From 2001 to 2013 in France.

BACKGROUND: We aimed to describe features of Escherichia coli meningitis in a large population of children and the molecular characteristics of the involved strains to determine factors associated with severe disease or death. METHODS: Between 2001 and 2013, a prospective national survey collected data for 325 children hospitalized with E. coli meningitis. The national reference center genetically characterized 141 isolates. RESULTS: Among the 325 cases, 65.2% were term, 22.4% late preterm, and 12.5% very/extremely preterm infants. Escherichia coli meningitis was 7-fold more frequent in preterm than term infants. Median age at diagnosis was 14 days; 71.1% of infants were neonates, with 2 peaks of infection at age 0-3 days (mostly preterm neonates) and 11-15 days (mostly term neonates); 8.9% were >89 days old. In total, 51.1% patients were considered to have severe disease, and 9.2% died. B2.1 phylogenetic subgroup (56%) and O1 serogroup (27.7%) were the most frequently identified. On multivariate analysis, death was associated with preterm birth (odds ratio [OR], 3.3 [95% confidence interval {CI}, 1.3-8.4], P = .015 for late preterm infants; OR, 7.3 [95% CI, 2.7-20.9], P < .001 for very/extremely preterm infants) and cerebrospinal fluid (CSF) to blood glucose ratio <0.10 (OR, 15.3 [95% CI, 1.8-128.3], P = .012). Death was associated with uncommon O serogroup strains (P = .014) and severe disease with O7 serogroup (P = .034) and PapGII adhesin (OR, 2.3 [95% CI, 1.2-4.5], P = .015). CONCLUSIONS: In this large study of 325 cases of E. coli meningitis, risk factors of severe disease or death were preterm birth, severe hypoglycorrhachia, CSF/blood glucose ratio <0.10, and molecular characteristics of strains, which should help optimize therapeutic management.

Vitamin d deficiency reduces the immune response, phagocytosis rate, and intracellular killing rate of microglial cells.

Meningitis and meningoencephalitis caused by Escherichia coli are associated with high rates of mortality and neurological sequelae. A high prevalence of neurological disorders has been observed in geriatric populations at risk of hypovitaminosis D. Vitamin D has potent effects on human immunity, including induction of antimicrobial peptides (AMPs) and suppression of T-cell proliferation, but its influence on microglial cells is unknown. The purpose of the present study was to determine the effects of vitamin D deficiency on the phagocytosis rate, intracellular killing, and immune response of murine microglial cultures after stimulation with the Toll-like receptor (TLR) agonists tripalmitoyl-S-glyceryl-cysteine (TLR1/2), poly(I·C) (TLR3), lipopolysaccharide (TLR4), and CpG oligodeoxynucleotide (TLR9). Upon stimulation with high concentrations of TLR agonists, the release of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) was decreased in vitamin D-deficient compared to that in vitamin D-sufficient microglial cultures. Phagocytosis of E. coli K1 after stimulation of microglial cells with high concentrations of TLR3, -4, and -9 agonists and intracellular killing of E. coli K1 after stimulation with high concentrations of all TLR agonists were lower in vitamin D-deficient microglial cells than in the respective control cells. Our observations suggest that vitamin D deficiency may impair the resistance of the brain against bacterial infections.

Current concepts on the pathogenesis of Escherichia coli meningitis: implications for therapy and prevention.

PURPOSE OF REVIEW: Neonatal Escherichia coli meningitis continues to be an important cause of mortality and morbidity throughout the world. The major contributing factors to this mortality and morbidity include our incomplete knowledge on its pathogenesis and an emergence of antimicrobial-resistant E. coli. Recent reports of neonatal meningitis caused by E. coli producing CTX-M-type or TEM-type extended-spectrum ß-lactamases create a challenge, and innovative approaches are needed to identify potential targets for prevention and therapy of E. coli meningitis. RECENT FINDINGS: E. coli invasion of the blood-brain barrier is a prerequisite for penetration into the brain and requires specific microbial-host factors as well as microbe-specific and host-specific signaling molecules. Recent studies identified additional microbial and host factors contributing to E. coli invasion of the blood-brain barrier and elucidated their underlying mechanisms. Blockade of the microbial-host factors contributing to E. coli invasion of the blood-brain barrier was shown to be efficient in preventing E. coli penetration into the brain. SUMMARY: Continued investigation on the microbial-host factors contributing to E. coli invasion of the blood-brain barrier is needed to identify new targets for prevention and therapy of E. coli meningitis, thereby limiting the exposure to emerging antimicrobial-resistant E. coli.

Molecular epidemiology of Escherichia coli causing neonatal meningitis.

Escherichia coli is the second cause of neonatal meningitis which is a major cause of neonatal mortality and is associated with a high incidence of neurological sequelae. E. coli neonatal meningitis (ECNM) strains, as other extraintestinal pathogenic E. coli, mainly belong to the phylogenetic group B2 and to a lesser extent to group D, but are distributed in fewer clonal groups. One of these, the O18:K1:H7 clone is worldwide distributed meanwhile others such as O83:K1 and O45:K1 are restricted to some countries. Over the past few years, major progress has been made in the understanding of the pathophysiology of E. coli O18:K1:H7 neonatal meningitis. In particular, specific virulence factors have been identified and are known to be carried by ectochromosomal DNA in most cases. Molecular epidemiological studies, including characterization of virulence genotypes and phylogenetic analysis are important to lead to a comprehensive picture of the origins and spread of virulence factors within the population of ECNM strains. To date, all the known genetic determinants obtained in ECNM strains are not sufficient to explain their virulence in their globality and further studies on clonal groups different from the archetypal O18:K1:H7 clone are needed. These studies would serve to find common pathogenic mechanisms among different ECNM clonal groups that may be used as potential target for a worldwide efficacious prevention strategy.

Clinical characteristics of adult Escherichia coli meningitis.

The clinical characteristics and therapeutic outcomes of adult meningitis due to Escherichia coli alone have not been examined adequately. In this study, we analyzed the clinical and laboratory data of 15 adult patients with monomicrobial E. coli meningitis. The 15 patients, collected over a period of 18 years (January 1986-December 2003), included 7 men and 8 women, aged 45-77 years. They accounted for 5% (15/306) of our adult bacterial meningitis with single pathogen infection. This study also revealed that a post-neurosurgical state is the most important factor predisposing adult patients to develop E. coli meningitis. In this study, all of the tested E. coli strains showed their susceptibility to imipenem and/or meropenem, however, E. coli strains that are not susceptible to third-generation cephalosporin have emerged since 2001. As to the therapeutic results of these 15 cases, all 4 patients without appropriate antibiotic treatment died and the other 11 patients with appropriate antibiotic treatment showed a mortality rate of 27%. The emergence of third-generation cephalosporin non-susceptible E. coli strains in adult bacterial meningitis, as shown in this study, has caused a therapeutic challenge in choosing initial empirical antibiotics for treating adult patients with post-neurosurgical meningitis. Our results emphasize that the timely use of appropriate antibiotics is essential for the management of this potentially fatal central nervous system infection. However, it should be noted that the number of cases examined in this study is too small to reach a therapeutic conclusion regarding adult E. coli meningitis, and further large-scale studies will be needed for this purpose.

[Virulence factors associated with E. coli neonatal meningitis]. / Facteurs de virulence associés à E. coli responsable de méningite néonatale.

Escherichia coli K1 is the leading cause of gram-negative bacterial meningitis in neonates. It is associated with a mortality rate as high as 40%, and more than half of the survivors have neurologic sequelae. Bacterial meningitis is the result of bacterial translocation from gastrointestinal tract to the blood and from blood to the central nervous system. Successful crossing of the BBB by E. coli K1 requires (a) a high degree of bacteremia and (b) several E. coli determinants contributing to invasion of BMEC such as the K1 capsule, Sfa, Ibe proteins, and CNF1. A better understanding for the molecular basis of E. coli K1 penetration of the BBB could potentially lead to the development of novel therapeutic and preventative strategies for E. coli K1 meningitis.

Effect of hypothermia on brain cell membrane function and energy metabolism in experimental Escherichia coli meningitis in the newborn piglet.

We evaluated the anti-inflammatory and neuroprotective effects of hypothermia during the early phase of experimental Escherichia coli meningitis in the newborn piglet. Hypothermia significantly attenuated the meningitis-induced acute inflammatory responses such as increased intracranial pressure, decreased glucose level, increased lactate concentration, increased tumor necrosis factor-alpha level and leukocytosis in the cerebrospinal fluid. Decreased cerebral cortical cell membrane Na+,K+-ATPase activity and increased lipid peroxidation products, indicative of meningitis-induced brain damage, were significantly improved with hypothermia. Hypothermia also significantly improved the meningitis-induced reduction in brain ATP and phosphocreatine levels. In summary, hypothermia significantly attenuated the acute inflammatory responses and the ensuing brain injury in experimental neonatal bacterial meningitis.