Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

OpcA is an integral outer membrane adhesin protein from Neisseria meningitidis, the causative agent of meningococcal meningitis and septicemia. It binds to sialic acid (SA)-containing polysaccharides on the surface of epithelial cells. The crystal structure of OpcA showed that the protein adopts a 10-stranded beta-barrel structure, with five extensive loop regions on the extracellular side of the membrane. These form a crevice structure, lined with basic residues, which was hypothesized to act as the binding site for polysaccharide ligands. In the current study, a distinctly different OpcA structure has been obtained using crystals grown from a lipidic mesophase. Comparison of the two structures shows that the largest loop (L2), which closes over the end of the beta-barrel in the original crystal form, adopts a much more extended structure by reaching outward and away from the protein. The difference in conformation may be attributable to the absence of zinc ions from the crystallization conditions for the in meso crystal form: in the original structure, two zinc ions were bound to the external loops. Molecular dynamics (MD) simulations performed on the two OpcA models in a lipid bilayer environment demonstrated pronounced loop mobility. These observations support the view that the loop regions of OpcA are capable of a high degree of conformational flexibility. The original binding site for polysaccharide is not present in the in meso crystal form, and is disrupted during MD simulations. Docking analysis suggests a putative alternative location for the SA ligand in the new crystal form of OpcA.
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PMID:In meso crystal structure and docking simulations suggest an alternative proteoglycan binding site in the OpcA outer membrane adhesin. 1807 35

Meningococcal meningitis remains a life-threatening disease. Neisseria meningitidis is the leading cause of meningitis and septicemia in young adults and is a major cause of endemic bacterial meningitis worldwide. The Meningitis Cohort Study was a Dutch nationwide prospective observational cohort study of adults with community-acquired bacterial meningitis, confirmed by culture of cerebrospinal fluid, from October 1998 to April 2002. Patients underwent a neurologic examination at discharge, and outcome was graded with the Glasgow Outcome Scale. Serogrouping, multi-locus sequence typing, and susceptibility testing of meningococcal isolates were performed. The study identified 258 episodes of meningococcal meningitis in 258 patients. The prevalence of the classical triad of fever, neck stiffness, and change in mental status was low (70/258, 27%). When rash was added to the classical triad, 229 of 258 (89%) patients had at least 2 of 4 signs. Systolic hypotension was associated with rash (22/23 vs. 137/222, p = 0.002) and absence of neck stiffness (6/23 vs. 21/220, p = 0.05). Neuroimaging before lumbar puncture was an important cause of delay of therapy: antibiotics were not initiated before computed tomography (CT) scan in 85% of patients who underwent CT scan before lumbar puncture. Unfavorable outcome occurred in 30 of 258 (12%) patients, including a mortality rate of 7%. Neurologic sequelae occurred in 28 of 238 (12%) patients, particularly hearing loss (8%). Factors associated with sepsis and infection with meningococci of clonal complex 11 (cc11) are related with unfavorable outcome.
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PMID:Clinical features, outcome, and meningococcal genotype in 258 adults with meningococcal meningitis: a prospective cohort study. 1862 1

Worldwide, meningococcal meningitis and sepsis cause 500,000 cases of illness and 50,000 deaths annually. The increase in global travel activity has resulted in a change in the epidemiology of infectious diseases, and an accumulation of evidence now indicates a connection between pilgrimage and the spread of meningococcal serogroup W135. During the past decade a number of cases of meningococcal disease caused by serogroup W135 have been observed in West Africa. The epidemiology of meningococcal disease in the meningitis belt has changed and this calls for awareness when counselling travellers.
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PMID:[Global spread of meningococcal serogroup W135]. 1882 28

Streptococcus pneumoniae and Neisseria meningitidis can cause sepsis and meningitis. Several risk factors for pneumococcal and meningococcal disease have been identified, but the cause of basic differences in susceptibility between individuals and populations is unknown. Single-nucleotide polymorphisms are thought to explain interindividual differences in susceptibility. New technologies provide the opportunity to study the genetic basis of susceptibility to these diseases. In recent years, several studies have been published on these polymorphisms in pneumococcal and meningococcal disease, many with apparently conflicting results. Herein we provide a systematic overview of all polymorphisms studied for a relation with susceptibility to pneumococcal and meningococcal disease. We also propose an initiative to pool genetic data on pneumococcal and meningococcal meningitis in one biobank.
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PMID:Host genetic susceptibility to pneumococcal and meningococcal disease: a systematic review and meta-analysis. 1903 41

Neisseria meningitidis is a major cause of bacterial meningitis and sepsis worldwide. Lipopolysaccharide (LPS), a major component of the Gram-negative bacterial outer membrane, is sensed by mammalian cells through Toll-like receptor 4 (TLR4), resulting in activation of proinflammatory cytokine pathways. TLR4 recognizes the lipid A moiety of the LPS molecule, and the chemical composition of the lipid A determines how well it is recognized by TLR4. N. meningitidis has been reported to produce lipid A with six acyl chains, the optimal number for TLR4 recognition. Indeed, meningococcal sepsis is generally seen as the prototypical endotoxin-mediated disease. In the present study, we screened meningococcal disease isolates from 464 patients for their ability to induce cytokine production in vitro. We found that around 9% of them were dramatically less potent than wild-type strains. Analysis of the lipid A of several of the low-activity strains by mass spectrometry revealed they were penta-acylated, suggesting a mutation in the lpxL1 or lpxL2 genes required for addition of secondary acyl chains. Sequencing of these genes showed that all the low activity strains had mutations that inactivated the lpxL1 gene. In order to see whether lpxL1 mutants might give a different clinical picture, we investigated the clinical correlate of these mutations in a prospective nationwide observational cohort study of adults with meningococcal meningitis. Patients infected with an lpxL1 mutant presented significantly less frequently with rash and had higher thrombocyte counts, consistent with reduced cytokine induction and less activation of tissue-factor mediated coagulopathy. In conclusion, here we report for the first time that a surprisingly large fraction of meningococcal clinical isolates have LPS with underacylated lipid A due to mutations in the lpxL1 gene. The resulting low-activity LPS may have an important role in virulence by aiding the bacteria to evade the innate immune system. Our results provide the first example of a specific mutation in N. meningitidis that can be correlated with the clinical course of meningococcal disease.
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PMID:Naturally occurring lipid A mutants in neisseria meningitidis from patients with invasive meningococcal disease are associated with reduced coagulopathy. 1939 Jun 12

Neisseria meningitidis, an exclusive human pathogen, is a major cause of mortality due to meningococcal meningitis and sepsis in many developing countries. Three meningococcal serogroup B proteins, i.e. T-cell stimulating protein A (TspA), autotransporter A (AutA), and IgA-specific serine endopeptidase (IGA1) elicits CD4+ T-cell response and may enhance the effectiveness of meningococcal vaccines by acting as protective immunogens. A very limited data on T-helper cell epitopes in MenB proteins is available. Hence, in silico prediction of peptide sequences which may act as helper T lymphocyte epitopes in MenB proteins was carried out by NetMHCIIpan web server. HLA distribution analysis was done by using the population coverage tool of Immune Epitope Database to determine the fraction of individuals in various populations expected to respond to a given set of predicted T-cell epitopes based on HLA genotype frequencies. Six epitopic core sequences, two from each MenB proteins, i.e. AutA, TspA and IgA1 protease were predicted to associate with a large number of HLA-DR alleles. These six peptides may act as T-cell epitope in more than 95% of populations in 8 out of 12 populations considered. The T-cell stimulation potential of these predicted peptides containing the core epitopic sequences is to be validated by using laboratory experiments for their efficient use as peptide vaccine candidates against N. meningitidis serogroup B.
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PMID:In silico CD4+ T-cell epitope prediction and HLA distribution analysis for the potential proteins of Neisseria meningitidis Serogroup B--a clue for vaccine development. 2071 48

Meningococcal meningitis and septicemia are a persistent public health concern owing to the associated mortality and devastating long-term sequelae. People of all ages may be affected, with the disease burden being higher in at-risk groups. Vaccination is the most rational approach to the prevention of invasive meningococcal disease. A novel quadrivalent meningococcal (Men) serogroup A, C, W-135 and Y polysaccharide-protein conjugate vaccine (MenACWY-CRM), has recently been licensed for use in individuals aged at least 11 years old in the USA, Canada and Europe. One dose of MenACWY-CRM is well tolerated, and induces robust immunity to all constituent vaccine serogroups in 11-65 year old individuals. MenACWY-CRM was found to be noninferior to the quadrivalent meningococcal ACWY-diphtheria toxoid glycoconjugate vaccine, which is also licensed in the USA and Canada. In Europe, MenACWY-CRM is the first quadrivalent meningococcal glycoconjugate vaccine available to provide broader protection against Neisseria meningitidis serogroups A, C, W-135 and Y.
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PMID:Novel quadrivalent meningococcal A, C, W-135 and Y glycoconjugate vaccine for the broader protection of adolescents and adults. 2113 85

Meningococcal meningitis and septicemia are serious infections with significant morbidity and mortality. A sensitive affordable test is required to provide evidence of meningococcal disease at the earliest opportunity to improve local management and give early warning of potential outbreaks of disease. Culture of organisms is considered the gold standard for diagnosis but is slow (24 h or more) and increasingly influenced by prior antibiotic treatment. Recently, the development of polymerase chain reaction (PCR) has improved diagnosis but this sensitive assay is costly, is not available at most primary care institutions and is not feasible for developing countries. Conventional latex agglutination (LA) enables rapid detection of bacterial antigen in cerebrospinal fluid (CSF) (1,2) and can also be used to test specimens of blood (3,4) or urine (5) and for serogroup determinations on primary cultures (6,7). We discuss here test-card agglutination and also describe a new technique based upon LA in an ultrasonic standing wave that retains the speed of direct antigen testing while significantly increasing sensitivity.
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PMID:Detection of meningococcal antigen by latex agglutination. 2133 37

The Gram-negative pathogen Neisseria meningitidis, is one of the leading causes of bacterial meningitis worldwide (1). The host range for this organism is restricted to humans, where it colonizes the mucosal epithelium of the upper airway. It occasionally disseminates causing invasive disease (sepsis, disseminated intravascular coagulation [DIC], meningitis). Epidemic meningococcal meningitis is a major health problem, most notably in sub-Saharan Africa. In 1999, an outbreak of meningococcal disease spread across Guinea-Bissau, a region that is part of what is commonly called the African meningitis belt (2). There were 2,169 reported cases and 404 deaths resulting from meningococcal disease in this outbreak from Jan. 1 to April 5, 1999. Also in 1999, there were reported outbreaks in Sudan (22,000 cases and 1,600 deaths) Rwanda (29 cases and 11 deaths), Angola (253 cases and 147 deaths), Ethiopia (126 cases and 4 deaths) and Senegal (2,709 cases and 372 deaths) (2). According to the World Health Organization (WHO), each year approx 500,000 cases of meningitis and 50,000 deaths are attributable to N. meningitidis worldwide. In the United States, meningococcal disease is less common, although small outbreaks are reported each year (3).
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PMID:Isolation and analysis of radiolabeled meningococcal endotoxin. 2133 60

Neisseria meningitidis causes significant disease in the form of severe sepsis syndrome or meningococcal meningitis. Owing to the susceptibility of the immune system in early life, the risk of disease after infection is significantly higher in infants. Thus far, vaccines targeted against meningococcal serogroups have struggled to provide lasting protection in young children. Even conjugate vaccines that are now routinely used in the immunization of infants require multiple dosing and the duration of protection has been shown to wane over time and require repeated booster doses. After briefly summarizing the current epidemiology according to age and serogroup, this article will consider the reasons for poor immunogenicity of vaccines in infants and will discuss the relative efficacy of the different vaccine types in this age group. It will then go on to consider strategies for optimizing the protection of infants against meningococcal disease.
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PMID:Challenges for development of meningococcal vaccines in infants and children. 2143 1


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