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Microbiology and pathobiology of Neisseria meningitidis

Microbiology and pathobiology of Neisseria meningitidis
Literature review current through: Jan 2024.
This topic last updated: Jan 08, 2024.

INTRODUCTION — Infection with Neisseria meningitidis can produce a variety of clinical manifestations, ranging from transient fever and bacteremia to fulminant disease with death ensuing within hours of the onset of clinical symptoms. N. meningitidis is a common cause of community-acquired bacterial meningitis in both children and adults. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Causative organisms' and "Epidemiology of community-acquired bacterial meningitis in adults", section on 'Incidence'.)

Mortality can be very high in patients with meningococcal disease if the infection is not treated appropriately, and long-term sequelae can be severe even in successfully managed cases due primarily to difficulty in managing the endotoxin-induced vascular collapse frequently induced by this organism. (See "Treatment and prevention of meningococcal infection", section on 'Prognosis'.)

The microbiology and pathobiology of N. meningitidis will be reviewed here. The epidemiology, clinical features, diagnosis, treatment, and prevention of meningococcal infections are discussed separately. (See "Epidemiology of Neisseria meningitidis infection" and "Clinical manifestations of meningococcal infection" and "Diagnosis of meningococcal infection" and "Treatment and prevention of meningococcal infection" and "Meningococcal vaccination in children and adults".)

HISTORY — Meningococcal disease was first described in 1805 after an epidemic of meningitis in Geneva. It was not until 1882 that the pathogen responsible for this disease was first isolated from the cerebrospinal fluid of an infected patient. The fact that the organism could be carried in the nasopharynx of healthy individuals was first recognized in 1890. In 1909, immunologically distinct serotypes of the meningococcus were identified. This established the basis for serum therapy, which was instituted by Flexner in 1913 [1].

Meningococcal epidemics among military recruits were a major consequence of military mobilization. As a result, the military participated in a number of important studies dealing with meningococcal disease, including the development of chemoprophylactic and immunologic methods to prevent infection. During World War I, the British army recognized that the frequency of carriage of the case strain rose prior to and during epidemics. With the advent of sulfonamides as an early antimicrobial treatment for meningococcal disease, the United States army used chemoprophylaxis with sulfonamides to dramatically reduce the incidence of disease among recruits during World War II. After the war, the availability of penicillin G greatly improved the treatment of meningococcal meningitis and sepsis, resulting in a substantial drop in mortality rates.

In 1963, the first reports of resistance to sulfonamides appeared at Fort Ord, California, among military recruits. Nasopharyngeal carriage could no longer be controlled with sulfonamides. During the Vietnam War, the incidence of meningococcal infection at some of the recruit training centers reached epidemic levels. The United States military continued to pursue chemoprophylaxis, which led to the identification of rifampin and minocycline as effective agents. The United States army also played a major role in the development of the meningococcal capsular polysaccharide vaccine, which was successful in preventing meningococcal disease in vaccinated recruits [2]. (See "Meningococcal vaccination in children and adults".)

MICROBIOLOGY — N. meningitidis is a gram-negative diplococcus approximately 0.7 to 1 micron in diameter. The adjacent sides are somewhat flattened. The organism is aerobic or facultatively anaerobic. When grown anaerobically, it requires nitrite as an electron acceptor. The meningococcus produces an oxidase that will oxidize the colorless dye tetramethyl-p-phenylenediamine to a bright purple color. This oxidase test has been used in the initial identification of the organism.

The meningococcus can use both glucose and maltose; oxidative metabolism of these sugars produces an acid. The shift in pH caused by this reaction has been traditionally used to differentiate meningococci from gonococci, which fail to oxidize maltose.

Meningococci can be subdivided into serogroups based upon distinct capsular polysaccharides; eight serogroups most commonly cause infections in humans (A, B, C, X, Y, Z, W135, and L). The genomes of numerous disease-causing meningococcal strains have been sequenced.

The use of transposon mutagenesis has identified 73 genes in serogroup B N. meningitidis that are essential for maintaining bacteremia [3]. This is an important issue since establishment and maintenance of bacteremic disease is required for all of the pathologic sequelae of meningococcal infection.

The meningococcus is considered a fastidious organism. Successful isolation from clinical sites such as blood and cerebrospinal fluid (CSF) necessitates care in handling the sample. The organism is highly susceptible to cold, high pH, and drying; as a result, specimens must be processed quickly.

Samples from normally sterile sites should be inoculated on nonselective enriched media, such as chocolate agar, and incubated in a moist environment at 37ºC under an atmosphere of 3 to 10 percent CO2. Selective media such as Thayer-Martin can enhance the isolation of the meningococcus from sites such as the pharynx, which are colonized by multiple bacterial species. This media contains antibiotics such as vancomycin, colistin, and nystatin, which do not inhibit the growth of the meningococcus but prevent growth of other gram-negative bacteria, gram-positive bacteria, and yeast.

Because the outcome of meningococcal infection is related to the rapidity with which antimicrobial and supportive therapy is initiated, a number of approaches have been taken to decrease the time to diagnosis. The use of specific anticapsular antisera in coagglutination systems has been used successfully in the early identification of N. meningitidis infection of the CSF. Polymerase chain reaction can also identify N. meningitidis in clinical samples [4].

PATHOBIOLOGY — N. meningitidis exclusively infects humans. The pathobiology of meningococcal infection is related to both nasopharyngeal colonization and a variety of virulence factors.

Nasopharyngeal carriage — Colonization of the nasopharyngeal surface by N. meningitidis is a prerequisite for the development of systemic infection. The only exceptions are the rare occurrences in which N. meningitidis is accidentally inoculated parenterally either in the laboratory or in the clinical setting.

Colonization of the nasopharynx occurs by inhalation of aerosolized particles containing meningococci. The nasopharynx is a mixed epithelial surface containing ciliated, secretory, and nonciliated, nonsecretory cells. Adenoids and tonsils serve as associated lymphoid tissues. These structures have mucosal surfaces that are covered with typical upper airway epithelium to which N. meningitidis can attach via adhesion proteins and then invade.

Studies indicate that most carrier strains lack capsular production. The loss of capsule may result from downregulation of capsule gene expression, phase variation in the capsule synthesis genes, or inactivation of genes in the capsule gene cluster. Loss of capsule appears to be crucial in meningococcal biology, as intimate adhesion on human mucosal surfaces and formation of microcolonies can then be mediated by adhesins such as type IV pili [5].While most meningococcal strains isolated from patients with meningococcal disease belong to a limited number of clonal types, strains isolated from carriers comprise numerous clonotypes, with a small proportion of the strains representing invasive clones [6].

Virulence factors — N. meningitidis uses a variety of virulence factors to adhere to and invade human epithelial and endothelial cells and to evade the human immune response [7]. These include phase variation, antigenic variation, and molecular mimicry of human antigens.

The principal virulence factors that have been identified to date include:

Pili, also called fimbria

Opacity proteins

Lipooligosaccharide

Capsular polysaccharide

Factor H binding protein

Pili (fimbria) — The pili of N. meningitidis are attachment organelles that undergo phase and antigenic variation. The pili of pathogenic Neisseria are composed of a pilin subunit that is encoded in the expression locus. Other incomplete copies of pilin genes are found in silent loci. The genes in the expression and silent loci undergo frequent recombinational events, causing an extraordinarily high rate of antigenic variation.

In addition to the principal pilus subunit (pilin or PilE), N. meningitidis produces low quantities of a phase-variable PilC protein that is implicated in pilus biogenesis and pilus-mediated epithelial cell adherence [8,9]. PilC protein, isolated from a strain of gonococcus that overproduces the protein, interacts specifically with human epithelial cells [10]. Binding of purified PilC effectively competes with pilus-mediated attachment of both N. gonorrhoeae and N. meningitidis. When fluorescent beads were coated with purified pili from a piliated mutant deficient in PilC, adherence to epithelial cells was abrogated; pretreatment with purified PilC restored adherence [11].

Pili are posttranslationally modified by addition of either an O-linked trisaccharide, Gal (beta 1,4) Gal (alpha 1,3) 2,4-diacetamido-2,4,6-trideoxyhexose, or an O-linked disaccharide Gal (alpha 1,3) GlcNAc [12]. Other studies indicate that phosphorylcholine posttranscriptionally modifies meningococcal pili [13]. A study suggests that pilus interaction with epithelial cells modifies gene transcription of a meningococcal transferase, which alters these structures and facilitates colonization and invasion [14]. The phosphorylcholine residue on pili interacts with the platelet-activating factor receptor, which initiates cell entry by the meningococcus [15].

Immunogold electron microscopy using antisera raised against purified PilC and synthetic peptides located PilC at the tip of gonococcal pili [10]. The tissue receptor for the pili of pathogenic Neisseria is thought to be CD46 (also called membrane cofactor protein) [16].

Pili may trigger cell signal mechanisms within epithelial cells. As an example, purified pili from an adherent strain led to an increase in cytosolic free calcium, whereas those from a low affinity binding mutant did not [17]. Antibodies against CD46 blocked intracellular calcium release.

Opacity proteins — Invasive and colonizing isolates of N. meningitidis express one or more of a family of closely related opacity proteins, such as Opa and Opc, on their outer membranes [18,19]. As the organism moves closer to the cells, these proteins play a role in attachment and perhaps in defining tissue specificity of the organism [19].

Studies have been performed with several variants expressing different Opa (OpaA, OpaB, OpaD) and Opc proteins with the following findings.

Analysis of sequence diversity among opa genes from hyperinvasive meningococcal strains, representing the seven most common disease-causing clonotypes, identified particular Opa protein variants that were consistently associated with each of the clonotypes over long time periods often spanning decades [20]. These observations suggest that particular Opa proteins confer fitness to invasive clonotypes and that these Opa proteins should be included in new vaccine formulations.

Opc was the most efficient protein for increasing bacterial interaction with endothelial cells [21]. In contrast, OpaB enhanced attachment to human epithelial cells to at least the same degree as Opc. The interaction with epithelial cells was inhibited by monoclonal antibody directed against OpaB.

Opc can bind to heparan sulfate proteoglycans on epithelial cells [22]. Opa28 strains that do not have Opc also bound to proteoglycans and, in contrast with Opc, to carcinoembryonic antigen (CEA) receptors. Mutants lacking both Opc and Opa28 were unable to bind to either of these receptors.

Surface sialic acids on capsule and lipo-oligosaccharide (LOS) influence attachment and entry to epithelial cells. The Opc interaction with the proteoglycan receptor is decreased when sialic acid is present on the surface of the organism [22]. In addition, Opa-mediated interactions are significantly reduced or eliminated in mutants expressing capsule or sialylated LPS [21].

Environmental factors controlling LOS and capsule phenotype affect the invasiveness of N. meningitidis strains. This effect may be based upon the ability to downregulate outer membrane protein-mediated binding to cells.

Lipo-oligosaccharide — The LOS of N. meningitidis is analogous to the lipopolysaccharide (LPS) of enteric gram-negative bacilli, although there are a number of structural differences between LOS and LPS [23]. As an example, LOS lacks the repeating O-antigen of the LPS.

LOS is generally present on gram-negative pathogens (pathogenic Neisseria and Haemophilus, H. ducreyi, Moraxella, Campylobacter, and Bordetella) that infect nonenteric surfaces; some Campylobacter species can also affect the gastrointestinal tract. The oligosaccharide portions of LOS contain structures that mimic human tissue antigens (eg, paragloboside, pk, the i antigen, Lewis X, and sialyl-Lewis X) [24]. LOS interacts with a variety of cells including macrophages, neutrophils, and endothelium to initiate the release of inflammatory mediators of the shock state [25-30]. These mediators include tumor necrosis factor-alpha, interleukin-1 and -6, and interferon-gamma. The symptoms of meningococcal sepsis are typically caused by LOS acting as an endotoxin and activating proinflammatory cytokine pathways in the host [31].

In some strains of pathogenic Neisseria, the LOS is the basis of resistance to complement-mediated lysis using human serum. The meningococcal LOS is serologically diverse, as at least 12 different LOS serotypes have been identified [32]. The chemical structures of the oligosaccharide portion of all 12 LOS serotypes have been elucidated. Many of the biosynthesis genes necessary for the production of the oligosaccharide portion of the LOS have been identified and a number of mutants have been created.

The lipid A portion of meningococcal LOS is structurally similar to the lipid A of Enterobacteriaceae LPS, which is the endotoxin moiety of these organisms. It contains the typical dihexosamine backbone structure with two phosphate head groups, and phosphoethanolamine is frequently present as a component of the head groups. Attached to the dihexosamine backbone through amide and ester linkages are four hydroxymyristic acid moieties; two of these are substituted with lauric acid at the 3 position [33].

The enzyme for the acylation of lipid A is encoded by the lpxL1 gene, and mutations in this gene result in an underacylated and inactivated lipid A [34]. Meningococcal infections caused by isolates possessing lpxL1 mutations have been associated with reduced cytokine production, less severe disease in patients with meningococcal meningitis (including less rash and higher platelet counts, consistent with less activation of tissue factor-mediated coagulopathy), and chronic meningococcemia [31,34].

The highest plasma levels of endotoxin measured in sepsis have been found in patients with meningococcemia. The ability of the organism to shed its outer membrane in bleb or vesicle-like structures is the primary factor in producing these high levels of endotoxin [35]. Strains of meningococcal serogroups A, B, and C release membrane blebs in the log, but not the lag, phase of growth. The release of endotoxin in the form of membrane blebs is not unique to the meningococcus. Similar mechanisms for the release of endotoxin have been documented in a number of other gram-negative bacteria including Salmonella, Shigella, Escherichia coli, Citrobacter, and Haemophilus spp. However, the degree of blebbing in these other species is considerably less than that seen with meningococcus.

Capsular polysaccharides — Bacterial capsular polysaccharides are polyanionic, well-hydrated structures that provide a physical defense barrier around the bacterium and may also determine access of molecules and ions to the bacterial cell outer membrane. The capsular polysaccharides of the meningococcus are highly charged, hydrophilic structures that act as a barrier to phagocytosis or complement-mediated lysis.

The genes for capsule production are contained within a single locus of approximately 18 kb. The locus is described as comprising three regions [36]. Regions 1 and 3 are common to all capsular types: region 1 encodes the "common" functions of capsule export, and region 3 probably encodes control functions. Region 2 differs among the capsule types and is responsible for encoding the functions for synthesis of the specific capsule. The common biochemical properties of these capsules and genetic organization of their production has led to their classification as type II capsules.

Serogrouping of meningococcal strains into at least 13 serogroups is based upon the capsular polysaccharide type. The overwhelming majority of disease worldwide is caused by five serogroups: A, B, C, Y, and W135. The immunogenicity of the group A, C, Y, and W135 polysaccharides in humans appears to be a function of their molecular size. The meningococcal B capsule has an alpha 2,8-linked polysialic acid structure that is similar to human intracellular adhesion molecules (ICAMs); it is believed that it is a very poor immunogen because it is a mimic of these ICAMs [37]. (See "Meningococcal vaccination in children and adults", section on 'Serogroup B vaccines'.)

Changing expression of the capsular polysaccharide appears to be important in the pathogenesis of meningococcal infection. Since the capsule acts as an antiphagocytic mechanism, its expression hinders interaction with epithelial cells. The meningococcus appears to downregulate capsular expression upon contact with epithelial cells [19,38,39]. This change may facilitate colonization and entry into nasopharyngeal epithelial cells [19].

This is in contrast to the observation that capsule expression is important for meningococcal survival within human cells [40]. In vitro assays suggest that unencapsulated meningococci are more susceptible to the antibacterial effects of cationic antimicrobial peptides than encapsulated meningococci. The same studies demonstrated upregulation of capsular biosynthesis genes during intracellular infection.

In a time period coinciding with the introduction of the conjugate meningococcal vaccine, capsular switching, a mechanism by which meningococcal isolates alter the antigenic profile of their polysaccharide capsules, has been shown to occur [41]. There is no evidence that it has impacted the efficacy of the currently formulated vaccine, but this does require ongoing population-wide surveillance since it could result in reduced vaccine efficacy. (See "Meningococcal vaccination in children and adults".)

Genetic diversity — In addition to capsular serotyping, meningococcal strains can be typed into sequence types, which is based on the alleles of seven housekeeping genes using multi-locus sequence typing (MLST) [42]. Lineages with sequence types sharing four or more alleles can be grouped into a single clonal complex. Certain clonal complex lineages have been associated with epidemics and outbreaks on a global scale. These lineages (of which there are 11) have been called hyperinvasive lineages [42]. The virulence of these lineages is thought to be based on nutritional factors, but this has not been confirmed.

Protein glycosylation — Glycosylation of proteins is a post-translational modification associated with crucial biological processes implicated in host-pathogen interactions. A variety of glycosylated proteins have been identified in Neisseria species; the PilE subunit of the pilin and the nitrate reductase AniA are the best characterized neisserial glycoproteins [43].

Human factor H-binding protein — Human factor H-binding protein is component of the meningococcal B vaccines. Human factor H binds in a highly specific manner to the human factor H-binding protein on the surface of the meningococcus. Human factor H is important in downregulation of the alternative complement system. On the meningococcal surface, it acts to degrade complement component C3, enhancing the organism's ability to resist the effects of complement-mediated lysis [44,45]. Antibody directed against the human factor H-binding protein prevents factor H binding. This is the basis for the efficacy of this protein as a component of the meningococcal B vaccines.

Cell entry — Upon contact with epithelial cells, the meningococcus initiates cytoskeletal changes within the cell, such as cortical actin rearrangements [8,18]. Adhesion mediated by pili, Opc, and OpaA can trigger these rearrangements, whereas nonadherent strains do not [8,18].

Attachment of the meningococcus to the epithelial surface is followed by a process that resembles receptor-mediated endocytosis. The bacteria are incorporated into vacuoles and then transported to the basolateral surface of the cell.

Only unencapsulated meningococci enter epithelial cells, and capsular biosynthesis ceases as the meningococcus enters such cells [39,46]. This change is mediated at least in part by reversible inactivation of essential sialic acid biosynthesis genes [39,46].

Survival within epithelial cells — The factors that permit survival of N. meningitidis within epithelial cells are not well understood. Type 2 IgA1 protease, produced by the meningococcus, increases degradation of lysosome-associated membrane protein 1 (LAMP1), a membrane glycoprotein associated with endosomes and lysosomes; the increased degradation is mediated by the Neisseria type 2 immunoglobulin (Ig)A1 protease [47]. An IgA protease mutant strain that does not affect LAMP1 turnover grows poorly in epithelial cells compared with the wild-type strain [47].

The capsule may also be important for intracellular survival of N. meningitidis, as discussed above. (See 'Capsular polysaccharides' above.)

Studies employing whole-genome sequencing of strains isolated from nasopharyngeal carriage and the blood of patients with invasive meningococcal have started to elucidate genetic differences at these different sites [48-50]. Genes that were most frequently undergoing changes included those involved in pilus biosynthesis, restriction modification, and LPS biosynthesis, as well as the genes for the major outer membrane porin (por A) [48].

Interaction with phagocytic cells and the complement system — N. meningitidis has important interactions with phagocytic cells and the complement system, which influence pathogenicity and host defense:

Opacity proteins influence the interaction of N. meningitidis strains with polymorphonuclear leukocytes via Opa proteins and with monocytes via Opc [51]. (See 'Opacity proteins' above.)

Capsular biosynthesis ceases as the meningococcus enters epithelial cells (such as those in the nasopharynx), an effect that involves reversible inactivation of essential sialic acid biosynthesis genes. (See 'Capsular polysaccharides' above.)

In addition, sialic acid expression must be downregulated for interactions with phagocytic cells to occur [51,52]. Piliated, sialylated organisms expressing both Opa proteins and Opc, which is a common phenotype in nasopharyngeal isolates, can be internalized by phagocytes in the absence of antibody or complement [53]. In contrast, piliated, sialylated strains found in the bloodstream can adhere to epithelial cells but do not interact with phagocytic cells.

Group B N. meningitidis, a serogroup that expresses surface sialic acid, is particularly resistant to serum-mediated and phagocytic killing and does not bind mannose-binding lectin (MBL), a serum protein that activates the classical complement pathway [54]. In contrast, group B mutants from which sialic acid residues are removed demonstrate increased binding of both MBL and C4.

The importance of MBL for complement activation was illustrated in a study of patients with meningococcal disease [55]. The patients with MBL deficiency had lower levels of activation of various complement components as well as less severe disease, including milder disseminated intravascular coagulation, compared with non-MBL-deficient patients [55]. (See "Clinical manifestations of meningococcal infection".)

Factor H-binding protein (fHBP) on the meningococcal surface binds human factor H but not factor H of other mammalian species [56]. This property may explain why the meningococcus infects humans exclusively. When fHBP binds to human factor H, it degrades any human C3 deposited on the surface, thus protecting the organism from complement lysis [57]. Binding of complement factor H enhances survival of N. meningitidis in normal human serum [57,58]. FHBP is sparsely distributed on the surface of N. meningitidis, but immunization with fHBP provides high levels of bactericidal antibodies against the meningococcus [59]. Thus, fHBP has been developed as a vaccine antigen. (See "Meningococcal vaccination in children and adults", section on 'Serogroup B vaccines'.)

Biofilm formation by meningococcus — The meningococcus forms biofilm-like structures in continuous flow chambers [60]. One study suggested that a functional PilE and twitching motility facilitate, but are not absolutely necessary for, biofilm formation [60]. The role of biofilm formation in colonization and disease are not known.

SUMMARY

Infection with Neisseria meningitidis can produce a variety of clinical manifestations, ranging from transient fever and bacteremia to fulminant disease with death ensuing within hours of the onset of clinical symptoms. (See 'Introduction' above.)

Mortality can be very high in patients with meningococcal disease if the infection is not treated appropriately, and long-term sequelae can be severe even in successfully managed cases due primarily to difficulty in managing the endotoxin-induced vascular collapse frequently induced by this organism. (See 'Introduction' above.)

N. meningitidis is a gram-negative diplococcus approximately 0.7 to 1 micron in diameter. Meningococci can be subdivided into serogroups based upon distinct capsular polysaccharides; eight serogroups most commonly cause infections in humans (A, B, C, X, Y, Z, W135, and L). (See 'Microbiology' above.)

N. meningitidis exclusively infects humans. The pathobiology of meningococcal infection is related to both nasopharyngeal colonization and a variety of virulence factors. Colonization of the nasopharyngeal surface by N. meningitidis is a prerequisite for the development of systemic infection. (See 'Pathobiology' above.)

N. meningitidis uses a variety of virulence factors to adhere to and invade human epithelial and endothelial cells and to evade the human immune response. These include phase variation, antigenic variation, and molecular mimicry of human antigens. The principal virulence factors that have been identified to date include pili (also called fimbria), opacity (Opa, Opc) proteins, lipooligosaccharide, and capsular polysaccharide. (See 'Virulence factors' above.)

Upon contact with epithelial cells, the meningococcus initiates cytoskeletal changes within the cell, such as cortical actin rearrangements. Adhesion mediated by pili, Opc, and OpaA can trigger these rearrangements. (See 'Cell entry' above.)

N. meningitidis has important interactions with phagocytic cells and the complement system, which influence pathogenicity and host defense:

Opacity proteins influence the interaction of N. meningitidis strains with polymorphonuclear leukocytes via Opa proteins and with monocytes via Opc.

Factor H-binding protein (fHBP) on the meningococcal surface binds human factor H but not factor H of other mammalian species; when it does so, fHBP degrades any human C3 deposited on the surface, thus protecting the organism from complement lysis. Studies suggest that it may be a promising vaccine target.

Capsular biosynthesis ceases as the meningococcus enters epithelial cells (such as those in the nasopharynx), an effect that involves reversible inactivation of essential sialic acid biosynthesis genes. (See 'Interaction with phagocytic cells and the complement system' above.)

  1. Flexner S. THE RESULTS OF THE SERUM TREATMENT IN THIRTEEN HUNDRED CASES OF EPIDEMIC MENINGITIS. J Exp Med 1913; 17:553.
  2. Artenstein MS, Gold R, Zimmerly JG, et al. Prevention of meningococcal disease by group C polysaccharide vaccine. N Engl J Med 1970; 282:417.
  3. Sun YH, Bakshi S, Chalmers R, Tang CM. Functional genomics of Neisseria meningitidis pathogenesis. Nat Med 2000; 6:1269.
  4. Newcombe J, Cartwright K, Palmer WH, McFadden J. PCR of peripheral blood for diagnosis of meningococcal disease. J Clin Microbiol 1996; 34:1637.
  5. Tzeng YL, Thomas J, Stephens DS. Regulation of capsule in Neisseria meningitidis. Crit Rev Microbiol 2016; 42:759.
  6. Yazdankhah SP, Caugant DA. Neisseria meningitidis: an overview of the carriage state. J Med Microbiol 2004; 53:821.
  7. Rosenstein NE, Perkins BA, Stephens DS, et al. Meningococcal disease. N Engl J Med 2001; 344:1378.
  8. Rudel T, Boxberger HJ, Meyer TF. Pilus biogenesis and epithelial cell adherence of Neisseria gonorrhoeae pilC double knock-out mutants. Mol Microbiol 1995; 17:1057.
  9. Virji M, Makepeace K, Peak I, et al. Functional implications of the expression of PilC proteins in meningococci. Mol Microbiol 1995; 16:1087.
  10. Rudel T, Scheurerpflug I, Meyer TF. Neisseria PilC protein identified as type-4 pilus tip-located adhesin. Nature 1995; 373:357.
  11. Scheuerpflug I, Rudel T, Ryll R, et al. Roles of PilC and PilE proteins in pilus-mediated adherence of Neisseria gonorrhoeae and Neisseria meningitidis to human erythrocytes and endothelial and epithelial cells. Infect Immun 1999; 67:834.
  12. Power PM, Roddam LF, Rutter K, et al. Genetic characterization of pilin glycosylation and phase variation in Neisseria meningitidis. Mol Microbiol 2003; 49:833.
  13. Warren MJ, Jennings MP. Identification and characterization of pptA: a gene involved in the phase-variable expression of phosphorylcholine on pili of Neisseria meningitidis. Infect Immun 2003; 71:6892.
  14. Chamot-Rooke J, Mikaty G, Malosse C, et al. Posttranslational modification of pili upon cell contact triggers N. meningitidis dissemination. Science 2011; 331:778.
  15. Jen FE, Warren MJ, Schulz BL, et al. Dual pili post-translational modifications synergize to mediate meningococcal adherence to platelet activating factor receptor on human airway cells. PLoS Pathog 2013; 9:e1003377.
  16. Källström H, Liszewski MK, Atkinson JP, Jonsson AB. Membrane cofactor protein (MCP or CD46) is a cellular pilus receptor for pathogenic Neisseria. Mol Microbiol 1997; 25:639.
  17. Källström H, Islam MS, Berggren PO, Jonsson AB. Cell signaling by the type IV pili of pathogenic Neisseria. J Biol Chem 1998; 273:21777.
  18. Merz AJ, So M. Attachment of piliated, Opa- and Opc- gonococci and meningococci to epithelial cells elicits cortical actin rearrangements and clustering of tyrosine-phosphorylated proteins. Infect Immun 1997; 65:4341.
  19. de Vries FP, van Der Ende A, van Putten JP, Dankert J. Invasion of primary nasopharyngeal epithelial cells by Neisseria meningitidis is controlled by phase variation of multiple surface antigens. Infect Immun 1996; 64:2998.
  20. Callaghan MJ, Jolley KA, Maiden MC. Opacity-associated adhesin repertoire in hyperinvasive Neisseria meningitidis. Infect Immun 2006; 74:5085.
  21. Virji M, Makepeace K, Ferguson DJ, et al. Meningococcal Opa and Opc proteins: their role in colonization and invasion of human epithelial and endothelial cells. Mol Microbiol 1993; 10:499.
  22. de Vries FP, Cole R, Dankert J, et al. Neisseria meningitidis producing the Opc adhesin binds epithelial cell proteoglycan receptors. Mol Microbiol 1998; 27:1203.
  23. Kahler CM, Stephens DS. Genetic basis for biosynthesis, structure, and function of meningococcal lipooligosaccharide (endotoxin). Crit Rev Microbiol 1998; 24:281.
  24. Mandrell RE, Apicella MA. Lipo-oligosaccharides (LOS) of mucosal pathogens: molecular mimicry and host-modification of LOS. Immunobiology 1993; 187:382.
  25. Waage A, Brandtzaeg P, Halstensen A, et al. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med 1989; 169:333.
  26. Brandtzaeg P, Ovstebøo R, Kierulf P. Compartmentalization of lipopolysaccharide production correlates with clinical presentation in meningococcal disease. J Infect Dis 1992; 166:650.
  27. Girardin E, Grau GE, Dayer JM, et al. Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med 1988; 319:397.
  28. Brandtzaeg P, Kierulf P, Gaustad P, et al. Plasma endotoxin as a predictor of multiple organ failure and death in systemic meningococcal disease. J Infect Dis 1989; 159:195.
  29. Brandtzaeg P, Mollnes TE, Kierulf P. Complement activation and endotoxin levels in systemic meningococcal disease. J Infect Dis 1989; 160:58.
  30. Brandtzaeg P, Bryn K, Kierulf P, et al. Meningococcal endotoxin in lethal septic shock plasma studied by gas chromatography, mass-spectrometry, ultracentrifugation, and electron microscopy. J Clin Invest 1992; 89:816.
  31. Persa OD, Jazmati N, Robinson N, et al. A pregnant woman with chronic meningococcaemia from Neisseria meningitidis with lpxL1-mutations. Lancet 2014; 384:1900.
  32. Mandrell RE, Zollinger WD. Lipopolysaccharide serotyping of Neisseria meningitidis by hemagglutination inhibition. Infect Immun 1977; 16:471.
  33. Kulshin VA, Zähringer U, Lindner B, et al. Structural characterization of the lipid A component of pathogenic Neisseria meningitidis. J Bacteriol 1992; 174:1793.
  34. Fransen F, Heckenberg SG, Hamstra HJ, et al. Naturally occurring lipid A mutants in neisseria meningitidis from patients with invasive meningococcal disease are associated with reduced coagulopathy. PLoS Pathog 2009; 5:e1000396.
  35. Cesarini JP, Vandekerkove M, Faucon R, Nicoli J. [Ultrastructure of the wall of Neisseria meningitidis]. Ann Inst Pasteur (Paris) 1967; 113:833.
  36. Kroll JS, Moxon ER. Capsulation and gene copy number at the cap locus of Haemophilus influenzae type b. J Bacteriol 1988; 170:859.
  37. Finne J, Leinonen M, Mäkelä PH. Antigenic similarities between brain components and bacteria causing meningitis. Implications for vaccine development and pathogenesis. Lancet 1983; 2:355.
  38. Deghmane AE, Giorgini D, Larribe M, et al. Down-regulation of pili and capsule of Neisseria meningitidis upon contact with epithelial cells is mediated by CrgA regulatory protein. Mol Microbiol 2002; 43:1555.
  39. Hammerschmidt S, Hilse R, van Putten JP, et al. Modulation of cell surface sialic acid expression in Neisseria meningitidis via a transposable genetic element. EMBO J 1996; 15:192.
  40. Spinosa MR, Progida C, Talà A, et al. The Neisseria meningitidis capsule is important for intracellular survival in human cells. Infect Immun 2007; 75:3594.
  41. Harrison LH, Shutt KA, Schmink SE, et al. Population structure and capsular switching of invasive Neisseria meningitidis isolates in the pre-meningococcal conjugate vaccine era--United States, 2000-2005. J Infect Dis 2010; 201:1208.
  42. Maiden MC, Bygraves JA, Feil E, et al. Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms. Proc Natl Acad Sci U S A 1998; 95:3140.
  43. Gault J, Ferber M, Machata S, et al. Neisseria meningitidis Type IV Pili Composed of Sequence Invariable Pilins Are Masked by Multisite Glycosylation. PLoS Pathog 2015; 11:e1005162.
  44. Seib KL, Scarselli M, Comanducci M, et al. Neisseria meningitidis factor H-binding protein fHbp: a key virulence factor and vaccine antigen. Expert Rev Vaccines 2015; 14:841.
  45. McNeil LK, Zagursky RJ, Lin SL, et al. Role of factor H binding protein in Neisseria meningitidis virulence and its potential as a vaccine candidate to broadly protect against meningococcal disease. Microbiol Mol Biol Rev 2013; 77:234.
  46. Hammerschmidt S, Müller A, Sillmann H, et al. Capsule phase variation in Neisseria meningitidis serogroup B by slipped-strand mispairing in the polysialyltransferase gene (siaD): correlation with bacterial invasion and the outbreak of meningococcal disease. Mol Microbiol 1996; 20:1211.
  47. Lin L, Ayala P, Larson J, et al. The Neisseria type 2 IgA1 protease cleaves LAMP1 and promotes survival of bacteria within epithelial cells. Mol Microbiol 1997; 24:1083.
  48. Klughammer J, Dittrich M, Blom J, et al. Comparative Genome Sequencing Reveals Within-Host Genetic Changes in Neisseria meningitidis during Invasive Disease. PLoS One 2017; 12:e0169892.
  49. Alamro M, Bidmos FA, Chan H, et al. Phase variation mediates reductions in expression of surface proteins during persistent meningococcal carriage. Infect Immun 2014; 82:2472.
  50. Bårnes GK, Brynildsrud OB, Børud B, et al. Whole genome sequencing reveals within-host genetic changes in paired meningococcal carriage isolates from Ethiopia. BMC Genomics 2017; 18:407.
  51. McNeil G, Virji M. Phenotypic variants of meningococci and their potential in phagocytic interactions: the influence of opacity proteins, pili, PilC and surface sialic acids. Microb Pathog 1997; 22:295.
  52. Kahler CM, Martin LE, Shih GC, et al. The (alpha2-->8)-linked polysialic acid capsule and lipooligosaccharide structure both contribute to the ability of serogroup B Neisseria meningitidis to resist the bactericidal activity of normal human serum. Infect Immun 1998; 66:5939.
  53. Estabrook MM, Zhou D, Apicella MA. Nonopsonic phagocytosis of group C Neisseria meningitidis by human neutrophils. Infect Immun 1998; 66:1028.
  54. Jack DL, Dodds AW, Anwar N, et al. Activation of complement by mannose-binding lectin on isogenic mutants of Neisseria meningitidis serogroup B. J Immunol 1998; 160:1346.
  55. Sprong T, Mollnes TE, Neeleman C, et al. Mannose-binding lectin is a critical factor in systemic complement activation during meningococcal septic shock. Clin Infect Dis 2009; 49:1380.
  56. Granoff DM, Welsch JA, Ram S. Binding of complement factor H (fH) to Neisseria meningitidis is specific for human fH and inhibits complement activation by rat and rabbit sera. Infect Immun 2009; 77:764.
  57. Madico G, Welsch JA, Lewis LA, et al. The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance. J Immunol 2006; 177:501.
  58. Welsch JA, Ram S, Koeberling O, Granoff DM. Complement-dependent synergistic bactericidal activity of antibodies against factor H-binding protein, a sparsely distributed meningococcal vaccine antigen. J Infect Dis 2008; 197:1053.
  59. Beernink PT, Leipus A, Granoff DM. Rapid genetic grouping of factor h-binding protein (genome-derived neisserial antigen 1870), a promising group B meningococcal vaccine candidate. Clin Vaccine Immunol 2006; 13:758.
  60. Lappann M, Haagensen JA, Claus H, et al. Meningococcal biofilm formation: structure, development and phenotypes in a standardized continuous flow system. Mol Microbiol 2006; 62:1292.
Topic 1276 Version 22.0

References

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