Introduction:
Bacterial meningitis is the leading cause of central nervous system (CNS) infection. The blood–brain barrier (BBB) protects the CNS from most bacteria that may have reached the
bloodstream. Most of the few types of bacteria, which can cross BBB to invade the meninges,
are extracellular pathogens: Escherichia coli K1 and Streptococcus agalactiae (Group B Streptococcus) in the newborn, N. meningitidis, Haemophilus influenzae type b, and Streptococcus pneumoniae in children and adults.
Bacterial meningitis is a devastating disease occurring worldwide with up to half of the survivors left with permanent neurological sequelae. Due to intrinsic properties of the meningeal pathogens and the host responses they induce, infection can cause relatively specific lesions and clinical syndromes that result from interference with the function of the affected nervous system tissue. Major pathogens include Streptococcus pneumonia, S. agalactiae (Group B Streptococcus), Neisseria meningitidis, and Escherichia coli K1, and also include a neglected zoonotic pathogen, Streptococcus suis. These neuroinvasive pathogens represent common themes of host–pathogen interactions, such as colonization and invasion of mucosal barriers, survival in the blood stream, entry into the central nervous system by translocation of the blood–brain and blood–cerebrospinal fluid barrier, and induction of meningeal inflammation, affecting pia mater, the arachnoid and subarachnoid spaces. acterial meningitis is a serious threat to global health. Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b are most commonly associated with bacterial meningitis in infants and adults. See Doran
In sub-Saharan Africa, also called the ‘meningitis belt’, N. meningitidis is a leading cause of large epidemics of meningococcal meningitis. Further bacteria that cause meningitis in children and adults include Group B Streptococcus (GBS), Escherichia coli K1, non-typhoideal Salmonella, Klebsiella spp., Staphylococcus aureus, Listeria monocytogenes, Mycobacterium tuberculosis and the neglected porcine zoonotic pathogen Streptococcus suis. Many of the meningeal pathogens are able to colonize the skin and different mucosal surfaces of healthy individuals. In certain cases, bacteria penetrate host cellular barriers to initiate a local infection that can result in systemic spread. An association between high-level bacteremia and development of meningitis has been suggested for some bacteria. See Doran
Neisseria meningitidis:
Introduction: Neisseria meninitidis appears as gram-negative diplococci and is commonly known as the meningococcus. The organisms causes the most serious form of acute meningitis and accounts for 15-20% of all meningitis cases. Most cases occur in young children, because vaccination of otherwise healthy children against this disease is not recommended until age 11. Because meningococci do not survive long in the environment, these bacteria are usually acquired through close contact with secretions or droplets. Meningococcal meningitis has a sporadic or epidemic incidence in late winter or early spring. The continuing reservoir of infection is humans who harbor the pathogen in the nasopharynx. The scene is set for transmission when carriers live in close quarters with nonimmune individuals, as might be expected in families, day care facilities, college dormitories and military barracks.
N. meningitidis usually resides in the human nasopharynx where it spends most of its life as a commensal microorganism by exploiting nutrients present on the mucosae. Crossing of teh epithelial cell layer of the nasopharnx is a rare event but, when it occurs, leads to invasion of the bloodstream, where bacteria are capable of eluding the immune system and of reaching the meninges. The ability of N. meningitidis to bind to ligands present on the surface of host cells allows the bacterium to easily enter in contact with the endothelial cell layer of the brain vessels and to form microcolonies. This interaction, mediated mainly by the type IV pili, modulates the endothelial cytoskeletons leading to the formation of docking structures similar to the ones elicited by leukocytes during extravasation and the consequent opening of the intercellular junctions. (Soriani, “unraveling Neisseria meningitidis pathogenesis: from functional genomics to experimental models” 2017).
Structure: N. meningitidis is a fastidious, encapsulated, aerobic gram-negative diplococcus.
Colonies are positive by the oxidase test and most strains utilize maltose. The phenotypic
classification of meningococci, based on structural differences in capsular polysaccharide,
lipooligosaccharide (LOS) and outer membrane proteins, is now complemented by genome
sequence typing (ST). See Stephens
The different sialic acid (serogroups B, C, Y, and W-135) and nonsialic acid (serogroup A) capsular polysaccharides expressed by Neisseria meningitidis are major virulence factors and are used as epidemiologic markers and vaccine targets. However, the identification of meningococcal isolates with similar genetic markers but expressing different capsular polysaccharides suggests that meningococcal clones can switch the type of capsule they express. See Wenger
Although 12 different strains with different capsular antigens exist, serotypes B, C and Y are responsible for most infection in the U.S. The bacterium enters the body via the upper respiratory tract, moves into the blood, rapidly penetrates the meninges and produces symptoms of meningitis.
In gram-negative bacteria, such as N. meningitidis, the subcapsular cell envelope consists of
an outer membrane (OM), a peptidoglycan layer, and a cytoplasmic or inner membrane.
Pathogenesis/Transmission: N. meningitidis is a common inhabitant of the human nasopharynx, and as such is a normal, saprophytic organism that is transmitted from person to person by direct contact. Only in a small proportion of colonized subjects does the bacteria invade the bloodstream where they are responsible for septicemia and/or meningitis, after crossing of the blood–brain barrier.
Meningitidis can be either encapsulated or not. However, N. meningitidis strains causing
invasive disease and isolated from sterile sites such as the blood or the CSF are almost
always encapsulated. The capsule is essential for the survival of the organism in the blood as
it provides resistance to antibody/complement-mediated killing and inhibits phagocytosis. The main meningococcal capsular polysaccharides associated with invasive disease are
composed of sialic acid derivatives, except for the serogroup A capsule, which consists of
repeating units of N-acetyl-mannosamine-1-phosphate. In N. meningitidis, Nacetylneuraminic acid (Neu5Ac), unlike in mammalian cells, is synthesized from Nacetylmannosamine (ManNAc) and phospoenolpyruvate without phosphorylated intermediates. Capsular genes are located in a single locus cps within the IHT-Al 24 kb virulence island that is divided in three regions A, B, and C.
Acquisition of meningococci through exposure to respiratory secretions and attachment on
human upper respiratory mucosal surfaces by N. meningitidis are the first steps in
establishing a human carrier state and invasive meningococcal disease. Meningococcal
carriage occurs in 8–25%. The adhesive properties of capsulate N. meningitidis are
mediated by pili.
Once inside the cerebrospinal fluid (CSF), bacterial multiplication is thought to be uncontrolled, owing to the local deficiency in complement and immunoglobulins, and despite the influx of polymorphonuclear leukocytes induced by the local inflammatory response. The small number of bacterial species capable of invading the meninges suggests that specific virulence factors are required for bacteria to enter the subarachnoidal space. Among the above-mentioned extracellular bacteria, N. meningitidis is the pathogen that once in the bloodstream, is able to invade the meninges the most effectively. It has been estimated that 63% of the cases of bacteremia owing to N. meningitidis are associated with meningitis. See Nassif
Streptococcus pneumoniae: (see outline)
Streptococcus pneumoniae also referred to as pneumococcus caseus the majority of bacterial pneumonias. Meningitis is also caused by this bacterium. It is the most frequent cause of community acquired meningitis and is also very severe. About 25% of pneymococcal meningitis patients will also ahve pneumococcal pneumonia. Two vaccines are available for S. pneumoniae, Prevanar which is recommended as part of the childhood immunization schedule and Pneumovax 23, which is available for adults. Crurent recommendations for unvaccinated adults call for initial vaccination with Prevnar, followed by Pneumovax 6-12 months later.
Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae, which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. See Van de Bek