The pathway of infection for any etiological agent of meningitis begins with the establishment of localized infection in the host1. Most meningeal pathogens are transmitted via the respiratory route. The pathogen must then evade host immune responses and enter the submucosa. Finally, the infectious agent must cross the blood-brain barrier and access the cerebro-spinal fluid (CSF). This is most often accomplished by invasion of the bloodstream and subsequent seeding of the CNS1.
Inflammatory cytokines and chemokines play an important role in the pathogenesis of bacterial meningitis. Exposure of cells to bacterial secretions results in the production of cytokines such as TNF-α and IL-11. These inflammatory mediators are believed to enhance the permeability f the blood-brain barrier and facilitate bacterial invasion of the CSF4. Secondary mediators such as IL-6, IL-8, nitric oxide, prostaglandins, and platelet activating factor amplify the effect, resulting in further vascular endothelial injury and the presence of bacteria in the subarachnoid space1.
Increased cytokine levels cause neutrophils to migrate from the bloodstream to the CSF, causing neutrophilic pleocytosis (an increased number of cells in the CSF) and contributing to vasogenic edema (increased water content in the brain)1. Eventual cerebral edema results in a decreased cerebral blood flow. This leads to an increase in lactate concentration due to anaerobic metabolism1. This process if left uncontrolled will result in permanent neuronal dysfunction.
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N meningitidis is a gram-negative aerobic diplococcus present in the nasopharynx of healthy individuals1. It is the leading cause of meningitis in children and young adults, accounting for 59% of cases1. Most cases of disease are caused by serogroups A, B, and C5. 
Meningococci must overcome host mucosal defenses and attach to the noncilliated columnar epithelial cells of the nasopharynx. Pili, found on the outer membrane of meningicocci, mediate the initial attachment by binding to the cell surface receptor CD464. Subsequent binding of the outer membrane proteins, Opa and Opc to CD66 and heparin sulfate proteoglycan receptors, respectively, lead to engulfment of the meningicocci by epithelial cells5. The bacteria are then able to traverse the mucosa via phagocytic vacuoles5. Alternatively, meningococci may enter the submucosa via damaged upper respiratory epithelium caused by smoking or environmental factors4.
Invasion and survival in the bloodstream are essent
ial for severe disease to occur. While colonization of the respiratory mucosa is common in healthy individuals, invasion of the bloodstream is very infrequent and not essential for bacterial survival or spread2. Meningococci that have entered the bloodstream either seed the CSF if multiplication proceeds slowly, or if multiplication is rapid, cause meningococcocemia and shock2.
Meningococci possess a number of virulence factors that contribute to immune evasion and pathogenesis. The meningococcal polysaccharide capsule inhibits osponophagocytosis and antibacterial factors, thus enhancing bacterial survival during invasion2. Meningococci also secrete an IgA protease and produce factors that inhibit ciliary activity in order to escape host mucosal defenses3.
The morbidity and mortality of meningococcal meningitis 
has been directly correlated to the amount of circulating lipooligosaccharide (LOS or endotoxin)2
. The presence of LOS contributes to the inflammatory cascade of cytokines that is characteristic of severe disease3. Meningococci are also prone to frequent blebing of the outer membrane. The blebs contain outer membrane protein as well as LOS that enhance the inflammatory cascade.
Throughout the process of meningococcal infection, the bacteria encounter many low-iron environments and have therefore developed ways to procure iron from the intracellular and extracellular environment4. Meningococci possess receptors that bind to hemoglobin within cells as well as human transferring and lactoferrin in the extracellular space.
Meningococci also exhibits significant genetic variability and are able to switch serogroups as another means of immune evasion5. This results in highly variable expression of outer membrane components, such as capsule, pili, and LOS4. The genetic switches are due to transformation of homologous DNA, strand mispairing, regulation of promoter regions, and transposable element movement4.
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S pneumoniae is a gram-positive coccus that is commonly found in the nasopharynx of healthy individuals1. It is the most common bacterial meningitis agent associated with basilar skull fractur
e and CSF leak. Since the advent of the H influenzae type B vaccine, S pneumoniae has become the major cause of bacterial meningitis in the U.S6. Mortality associated with pneumococcal meningitis is about 20%, higher than any other bacterial etiology7.
Pneumococcal invasion of the submucosa requires activation of nasopharyngeal epithelial cells and the presence of the polymeric IgA receptor, which is believed to bind the pneumococcal adhesion, CbpA6. The organism secretes an IgA protease that cleaves the hinge region of IgA, leaving it dysfunctional7. Once pneumococci enter the intravascular space, it must evade the alternative complement pathway and does so by means of its polysaccharide capsule7. Successful multiplication in the intravascular space is followed by invasion of the CSF.
Several virulence factors are involved in CNS invasion by pneumococci. Pneumolysin has been shown to damage endothelial cells and compromise the integrity of the blood-brain barrier6. The glycosidase, hyaluronidase degrades components of the extracellular matrix and also facilitates development of meningitis6. The pneumococcal cell wall components are primarily responsible for the proinflammatory responses characteristic of meningitis7.
Pneumococci invade the CSF through seeding of the choroid plexus (vascular complex that secretes the CSF) or direct extension from sinusitis (inflammation of the sinus) or otitis media (inflammation of the middle ear)1. A possible mechanism of invasion involves the teichoic acid component of the pneumococcal cell wall binding to PAF receptors of the endothelial cell surface7. These receptors are upregulated during the inflammatory response and facilitate bacterial crossing of the blood-brain barrier.
Recent studies have indicated that endogenous vasoconstrictors and endothelins contribute to decreased cerebral blood flow, leading to ischemia and cortical brain damage6. This necrotic damage to the cerebral cortex has also been attributed to reactive oxygen species that are part of the host defense against invading bacteria6. In addition, pneumococcal meningitis induces apoptosis of the hippocampus via mechanisms that are still under investigation6.
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H influenzae is a pleomorphic, gram-negative coccobacilli that is found in the normal upper respiratory tract flora of many healthy individuals1. Disease is caused primarily by the encapsulated type B strain. Although the advent of the HiB vaccine has resolved
the problem of HiB meningitis in the U.S., it still remains the leading cause of bacterial meningitis in the developing world6.
The encapsulated form H influenzae has the ability to penetrate the nasopharyngeal epithelium and directly invade blood capillaries10. The capsule protects the organism from phagocytosis and complement-mediated lysis10. Pili, or fimbriae, called Hia improves adherence to mucosal epithelium and is required for nasopharyngeal colonization10. The exact mechanism of mucosal invasion and spread to the CSF is poorly understood.
HiB produce several virulence factors associated with infection and disease. Although these bacteria do not produce endotoxin, they contain a lipopolysaccharide (LPS) component of the cell wall that contributes to pathogenesis11. All virulent strains of HiB also produce neuraminidase and IgA protease10.
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