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Neisseria meningitidis (Nm) (meningococcus) causes diseases that are globally distributed. Humans are the only natural host of Neisseria meningitidis. Currently, the meningococcal strains identified can be classified into 13 serogroups. The most prevalent human pathogenic serogroups include A, B, C, W, X and Y. N. meningitidis avoids host innate and adaptive immune response through high levels of antigenic variation. The pathogen breaches nasopharyngeal epithelium, entering the bloodstream and causing invasive meningococcal disease (IMD).
Figure 1. Schematic overview of meningococcal interactions at the epithelial barrier of the nasopharynx and the mode of barrier penetration
(Source: Hill DJ, et al. 2010)
Nm is a Gram-negative member of the family Neisseriaceae. It is an obligate human pathogen with a human host restricted relatedness to Neisseria gonorrhoeae and an encapsulated or unencapsulated aerobic diplococcus, "kidney" or "coffee bean" shaped, nonmotile (lacking flagella) which require oxygen for growth (aerobic). Neisseria meningitidis is fastidious with strict environmental requirements. This bacterium grows best at temperatures of 35–37°C and 5%–10% carbon dioxide. It will grow on many culture media. On blood agar, the colonies are gray, round, convex, non-hemolytic, smooth, moist, with clearly defined edges and a glossy surface.
Except for the IHT-A1 capsule gene locus, no specific core pathogenic genome has been identified in Neisseria meningitidis, suggesting that its virulence may depend on the strain's clonal group. The metabolic functions represent the core genome which accounts for around 70% of the total genome. Large genomic islands were identified between different strains, and these likely encode putative surface proteins and virulence factors. The IHT-A1 locus contains genes encoding capsule biosynthesis and transport, the IHT-A2 locus potentially encodes ABC transporters and secretory proteins, while the IHT-C locus probably encodes 30 open reading frames, including toxin homologs, phages, and possible virulence proteins. An additional characteristic of the Neisseria meningitidis genome are numerous genetic switches, such as slipped-strand mispairing and insertion sequence (IS) element movement, which allow fine regulation of expression of pathogenicity-related genes.
Neisseria meningitidis may be encapsulated or unencapsulated. Isolates from sterile sites that cause invasive disease are, however, almost always encapsulated. The capsule is important for bacterial survival in the bloodstream because it is resistant to antibody- and complement-mediated killing and inhibits phagocytosis. Antibodies to the capsule are important in preventing meningococcal disease. The capsule is also the target of the currently available polysaccharide vaccines and the newer conjugate vaccines (with the exception of serogroup B) and is used for classification of meningococcal serogroups.
Capsular polysaccharides of invasive Nm strains are largely composed of derivatives of sialic acid, except the serogroup A capsule, which is composed of repeating units of N-acetylmannosamine-1-phosphate. Nm converts Neu5Ac from ManNAc and phosphoenolpyruvate in a mechanism that involves a phosphorylated intermediate that is not observed in mammalian cells. Neu5Ac is the predominant sialic acid in humans and is known to play a role in cell and molecular recognition. Expression of Neu5Ac in the meningococcal capsule allows the organism to avoid host detection through molecular mimicry. The prototype example is the serogroup B capsule. This is a polymer of α(2–8)-linked sialic acid which has the same structure as the human fetal neural cell adhesion molecule (NCAM), which results in a particularly weak immune response against serogroup B capsules in humans.
Below the capsule is the cell envelope, which includes the outer membrane (OM), peptidoglycan layer and cytoplasmic membrane (inner membrane). The outer leaflet of the OM is composed mainly of lipopolysaccharide and protein, and the inner leaflet of phospholipids and proteins that regulate the passage of nutrients and metabolic products. The major phospholipid components of the Neisseria membrane are PE and, in varying amounts, PG, CL and PA.
The peptidoglycan of various Nm strains is up to two layers thick, and can vary in degree of cross-linking and O-acetylation. The average degree of cross-linking in meningococcal peptidoglycan is about 40% and is similar to that found in other Gram-negative bacteria. O-acetylation of peptidoglycan results in resistance to lysozyme and other peptidoglycan hydrolases. Peptidoglycan structure can be detected by components of the innate immune system.
The lipopolysaccharide (LPS) or lipooligosaccharide (LOS, endotoxin) is an important factor in bacterial adhesion as well as the activation of the innate immune system. In contrast to the enteric Gram-negative rods, meningococcal LOS is devoid of repeating O-antigen side chains. The Nm LPS is composed of three parts: lipid A, which contains the hydroxy fatty acid chains and phosphoethanolamine; the core oligosaccharide, which contains 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) and heptose residues; and a highly variable short oligosaccharide chain. Lipid A is the predominant determinant of the biological activity and toxicity of the endotoxin.
Meningococcal LOS attaches to various host innate immune cell (monocytes, dendritic cells) transport molecules and receptors, including LPS-binding protein (LBP), CD14, and MD2, a component of the TLR4 complex. This binding triggers the secretion of various cytokines like IL-6 and TNF-α, which at high levels can cause endothelial damage and capillary leakage. The level of LPS correlates directly with the severity of meningococcal disease. LPS also induces the release of chemokines, ROS, and NO.
Additionally, LOS plays an important role in resisting other host defenses. Due to the phosphoethanolamine structure on the lipid A head, Nm is resistant to cationic antimicrobial peptides (CAMPs). CAMPs are found in macrophages and neutrophils and can also be produced by epithelial cells on mucosal surfaces. These peptides contribute to host defense against microbial infection and innate immune responses through non-oxidative killing mechanisms and signaling functions.
Figure 2. Schematic review of Neisseria meningitidis surface molecules and their interactions with human host cell binding ligands
(Source: Hung MC, et al. 2013)
Nm typically spreads through respiratory transmission. After infection, clinical symptoms vary greatly in severity, ranging from persistent asymptomatic carriage to upper respiratory tract inflammation. In a small proportion of infected individuals, Nm invades the bloodstream, causing invasive disease. Before invasive disease manifests, patients usually experience upper respiratory symptoms, which may result from a preceding viral infection that creates favorable conditions for Nm infection or may be caused by Nm itself.
The most common clinical presentation of Nm infection is acute bacterial meningitis. Classic disease initially presents with 1 to 2 days of symptoms that mimic those of an upper respiratory tract infection. Rapidly progressing high fever, chills and other signs of systemic toxicity become apparent within a day. Characteristic petechiae or purpura appear on the skin, followed by severe headache, vomiting and signs of meningeal irritation. In fulminant patients, the onset is abrupt with high fever, and symptoms are so severe and rapidly progressive that death can occur within 24 hours. Three types of fulminant disease have been described: shock type, with circulatory failure and DIC; meningoencephalitis type, with severe neurological involvement; and mixed type, with features of both shock and meningoencephalitis types.
Children with bacterial meningitis are usually febrile and experience chills, vomiting, photophobia and severe headache. The most common clinical features are fever, headache, neck stiffness and vomiting. Older children present with more typical clinical features than younger children; younger age is associated with less obvious clinical features and signs of headache, photophobia, vomiting, and neck stiffness. In newborns and infants, the illness has a more gradual onset with fever, refusal to feed, irritability, and lethargy. A bulging fontanelle may be the primary sign of nervous system involvement, and Brudzinski's sign is often positive.
Infants and young children with epidemic cerebrospinal meningitis are more prone to have the disease complicated with ventriculitis, subdural effusion, and hydrocephalus. Sequelae of epidemic cerebrospinal meningitis are mostly cranial nerve damage. The nerve damage can cause hearing loss (mostly unilateral), blindness, and oculomotor nerve paralysis. Parenchyma of the brain damage can lead to paralysis, epilepsy, intellectual disability, and psychiatric abnormality.
The treatment of choice for meningococcal meningitis is penicillin G, amoxicillin or ampicillin. However, strains with reduced penicillin sensitivity have been reported from many countries. Until in vitro susceptibility results are available, meningococcal meningitis patients should be empirically treated with third-generation cephalosporins such as cefotaxime or ceftriaxone.
Conjugate vaccines generate a strong, long-lived, T cell-dependent immune response, which results in the formation of plasma cells and memory B cells. Vaccines are now available for five of the six major pathogenic serogroups (A, C, W, X and Y). The polysaccharide capsule of serogroup B is not immunogenic. Different vaccine strategies are required to prevent group B disease. Outer membrane vesicles (OMVs) are produced continuously by Gram-negative bacteria. The main antigen of Nm OMVs is the outer membrane porin protein PorA, however PorA is highly variable, which limits the use of OMV vaccines to protection against particular PorA variants with limited cross-protection. To broaden coverage, researchers have combined OMVs from two to three meningococcal strains, each expressing different PorA variants.
The genomic era has enabled reverse vaccinology, screening whole genome sequences to identify group B vaccine candidates such as NadA, NHBA, and factor H binding protein (fHbp), all included in the now-approved group B meningococcal vaccines. Traditional biochemical isolation methods have also confirmed fHbp as a key vaccine antigen.
Table 1. Meningococcal vaccines of current interest
| Vaccine | Type | Antigens included |
| Quadrivalent glycoconjugate | Conjugated polysaccharide-protein | ACWY |
| Pentavalent meningococcal vaccine (MnCV5) | Conjugated polysaccharide-protein | ACWYX |
| Meningococcal A conjugate | Conjugated polysaccharide-protein | A |
| 4CMenB | Protein (nonpolysaccharide) | fHbp (subfamily B only), NHBP, NadA, PorA (OMV MenZB) |
| MenB-FHbp | Protein (nonpolysaccharide) | Bivalent fHbp (sub families A and B) |
(Source: Read RC. 2019)
References
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