Neisseria meningitidis

Neisseria meningitidis is a fastidious, 0.2 to 0.8 µm, encapsulated, aerobic, immobile, Gram-negative diplococcus. Neisseria meningitidis, like Neisseria gonorrhoeae, belongs to the genus Neisseria in the family Neisseriaceae, which also includes the human pathogenic genera Eikenella and Kingella. In addition to N. meningitis, N. gonorrhoeae (causative agent of gonorrhoea) and, for differential diagnostic reasons, a number of apathogenic Neisseria species belonging to the normal flora of the pharynx are of medical importance in this family.

Colonies of Neisseria meningitidis are positive in the oxidase test. Most strains metabolize maltose.

Phenotypic classification of meningococci based on structural differences in capsular polysaccharide, lipooligosaccharide (LOS) and outer membrane proteins is complemented by genome sequence typing (ST). The genome of N. meningitidis serogroups A and B was completely sequenced back in 2000. The genome size is 2.2 million base pairs (Rouphael NG et al. 2012).

Humans are the only reservoir for N. meningitidis. The pathogen colonizes asymptomatic mucosal surfaces (nasopharynx) through a multifactorial process involving pili, "twitching motility," LOS, turbidity-associated and other surface proteins (Rouphael NG et al. 2012; Coureuil M et al. 2019). Thus, 5-10% of the population are asymptomatic germ carriers of meningococci. Person-to-person transmission of the germs is thought to occur by droplet infection or by direct or indirect oral contact (Hof H et al. 2019).

The species differentiation is based, among other things, on the different abilities of meningococci to cleave sugar.

Due to different antigenic structures of the capsular polysaccharides, Neisseria meningitidis can be divided into 12 serotypes: A, B, C,X,Y,Z,E,W, H, I, K, L. The most common serotype is B, which is responsible for sporadic cases in Europe (Hof H et al. 2019).

The pathogen enters the nasopharyngeal cavity by droplet infection. Primary adherence to epithelial cells probably occurs via pili. In this process, various outer membrane proteins (including Opa, Opc) play a special role. N. meningitis can then establish close contact with the host cell via Opa proteins. This interaction allows the bacteria to pass through the cell into the subepithelial tissue. This process occurs relatively quickly. Thus, the microorganisms can be detected within 24 h in the vicinity of local immune cells and vessels. In most cases, this nasopharyngeal infection passes unnoticed, subclinical.

After mucosal penetration, the bacterium can penetrate the vascular barrier. In the vascular system, meningococci are either eliminated by an interaction of bactericidal serum antibodies, complement factors, and phagocytosing cells, or they are able to multiply explosively. This initiates the bacteraemic phase.

Interaction of N. meningitidis with human endothelial cells leads to the formation of typical microcolonies, vascular injury, and in an extreme case, disseminated intravascular coagulation (Coureuil M et al.2019). Factors such as capsule formation or sialization of lipopolysaccharides cause , antigenically significant outer membrane proteins (e.g. Opa) to be masked. As a result, the bacteria are poorly recognized by the immune defense system. They are able to survive and multiply.

Neisseria meningitidis causes significant morbidity and mortality in children and young adults worldwide through epidemic or sporadic meningitis and/or septicaemia (Rouphael NG et al. 2012). In industrialized countries, the annual incidence of meningococcal infections is about 1 to 10 cases/100 000 population. It is higher in children < 2 years of age. In Germany, about 300 meningococcal diseases are registered. They occur preferentially in the winter and spring months (Hof H et al. 2019).

Developing countries: Meningitis epidemics are regularly reported from Africa (mainly Sahel Africa "meningitis belt" , China and South America. They cause many deaths. Serogroup A meningococci used to be the primary cause of these epidemics. Massive vaccination campaigns have pushed this serotype back. Currently, it is no longer observed in epidemics. Instead, infections with serotypes W,X and C are occurring more frequently (Hof H et al. 2019).

Virulence factors of N.meningitidis (Pizza M et al. 2014):

Adhesins: Adhesins or adhesion molecules allow the pathogen to bind to epithelial cells. They induce internalization, allowing the pathogen to overcome this barrier by the intracellular route.

Receptor for human transferrin: N. meningitides is not capable of forming siderophores. However, iron is essential for the growth of these bacteria. Instead, they form receptor proteins for transferrin. These have a stronger affinity for iron than transferrin. This affinity allows them to take over and process iron ions from transferrin in the organism.

Endotoxins: N. meningitides produces endotoxins that are capable of triggering the cytokine cascade, causing fever, coagulopathy, and shock. These toxins are toxic cell wall components, such as lipopolysaccharide (LPS) and others. These endotoxins activate macrophages, which secrete TNF-alpha. This leads to fever, toxic vasculitis, disruption of the coagulation system and bleeding.

IgA prote ases: IgA proteases cleave IgA immunoglobulins and inhibit the action of protective antibodies.

Polysaccharide capsule: A capsule protects the pathogen from phagocytosis and complementopsonization. The nature of the capsule surface prevents the formation of a functional convertase and the membrane-attack complex. This makes efficient C3b-mediated opsonization impossible.

Phase variation and antigenic variance: Phase variation, i.e. switching on and off of specific genes associated with antigenic variance (of surface molecules) plays an important role in meningococcal virulence. It can lead to abrupt changes in the phenotype and thus its antigenicity(antigenic mimicry).

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Immunity in M. meningitis: Elimination of the disease is complicated by the enormous diversity and antigenic variability of the pathogen, Neisseria meningitidis, one of the most variable bacteria in nature(Caugant A et al.2014).For natural immunity to meningococci, colonization with non-pathogenic N. lactamica and non-related but immunologically similar bacteria could be important.

Deficiencies in the complement system: The complement system and antibodies against the capsule (in B meningococci also against membrane proteins) play a critical role in the immune defense of invasive meningococcal disease, as activated complement leads to bacterial death by direct lysis or by opsonization and phagocytosis.

Individuals who undergo recurrent attacks of Neisseria infection have a high prevalence of familial deficiencies of terminal complement factors (see Immune Deficiencies Primary (Complement Deficiencies) below). This deficit results in the inability to form the membrane-attacking complex (C5-C9). However, the prevalence of terminal complement factor deficiency in the general population is very low (about 0.03%). On the other hand, approximately 50% of all affected individuals undergo meningococcal infection at some point in their lives. Patients with complement factor deficiency tend to have infections with the rarer serogroups W-135, X, Y, Z, and 29E.

Properdin Deficit: Individuals with properdin deficiency, a sex-related inherited disorder, have functional classical complement activation but impaired alternative activation. More than half of males in this group develop meningococcal disease, and the course is often fulminant with a fatal outcome.

Individuals with hypogammaglobulinemia, primary isolated IgM deficiency, or functional/organic asplenia are also at increased risk for sporadic meningococcal disease or for severe disease courses (see Waterhouse-Friderichsen syndrome below).

The course of meningococcal infection is acute. The incubation period is 2-5 days. After that, a severe clinical picture suddenly sets in with high fever, chills, headache and stiff neck. Bacteremia may lead to infection of the endothelia with microthrombosis. The release of toxic cell wall components (endotoxins; e.g., lipopolysaccharides) can lead to life-threatening disease states and septic shock. A clinical feature is the Waterhouse-Friderichsen syndrome with endoxin shock, consumption coagulopathy (purpura fulminans) and haemorrhagic necrosis of the adrenal cortex.

Neisseria meningitidis is detected in cerebrospinal fluid, nasal and throat swabs and blood. The test material must be processed quickly, as the pathogens are sensitive to cold. Gram-negative diplococci are visible intracellularly and extracellularly in the smear. N. meningitidis grows on media containing blood, carbon dioxide promotes growth. Differentiation from other neisseria is biochemical. Antigens of meningococci can be directly detected in the cerebrospinal fluid using a latex agglutination test.

Penicillin G remains the antibiotic of choice for meningococcal disease. Chloramphenicol and 3rd generation cephalosporins such as ceftriaxone also play a role.

Invasive meningococcal disease forms almost exclusively in people who lack protective, bactericidal antibodies directed against the infectious strain. In children in the first months of life, passively transmitted maternal antibodies play a role in protection. With the loss of maternal antibodies, susceptibility to infection increases with a peak at 6 to 12 months of age. It declines progressively thereafter, presumably because of colonization with closely related nonpathogenic bacteria such as N. lactamica, with avirulent N. meningitidis, or with other bacteria expressing surface antigens that cross-react with those of virulent meningococcal strains.

In some cases, meningococci remain confined to the blood, i.e., no inflammation of the meninges develops. The proliferation of meningococci in the blood (sepsis; coagulation disorders) is also life-threatening(Waterhouse-Friderichsen syndrome.). Ultimately, it has not yet been definitively clarified how meningococci cross the blood-brain barrier (Coureuil M et al.2019).

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