Neisseria meningitidis

Neisseria meningitidis is a fastidious, 0.2 to 0.8 µm large, encapsulated, aerobic, non-motile, gram-negative diplococcus. Like Neisseria gonorrhoeae, Neisseria meningitidis belongs to the genus Neisseria in the Neisseriaceae family, which also includes the human pathogenic genera Eikenella and Kingella. In addition to N. meningitidis, of medical interest in this family are N. gonorrhoeae (pathogen of gonorrhea) and, for differential diagnostic reasons, a number of apathogenic Neisseria species that belong to the normal flora of the pharynx.

The colonies of Neisseria meningitidis are positive in the oxidase test. Most strains utilize maltose.

The 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 already completely sequenced 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 carriers of meningococci. The transmission of germs from person to person presumably occurs through droplet infection or through direct or indirect oral contact (Hof H et al. 2019).

Species differentiation is based, among other things, on the different abilities of meningococci to break down 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 and 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. Various outer membrane proteins (e.g. Opa, Opc) play a special role in this process. N. meningitidis can then establish close contact with the host cell via Opa proteins. This interaction enables the bacteria to pass through the cell into the subepithelial tissue. This process takes place relatively quickly. The microorganisms can be detected within 24 hours in the vicinity of local immune cells and blood vessels. In most cases, this nasopharyngeal infection is subclinical and goes unnoticed.

After penetration of the mucous membrane, the bacterium can penetrate the vascular barrier. In the vascular system, the meningococci are either eliminated by an interaction of bactericidal serum antibodies, complement factors and phagocytizing cells, or they are able to multiply explosively. This initiates the bacteremic 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 the 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 system. They are able to survive and multiply.

Neisseria meningitidis causes significant morbidity and mortality in children and young adults worldwide due to epidemic or sporadic meningitis and / or septicemia (Rouphael NG et al. 2012). In industrialized countries, the annual incidence of meningococcal infections is around 1 to 10 cases per 100,000 inhabitants. It is higher in children < 2 years. Around 300 cases of meningococcal disease are registered in Germany. They prefer to occur in the winter and spring months (Hof H et al. 2019).

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

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

Adhesins: Adhesins or adhesion molecules enable the pathogen to bind to the epithelial cells. They induce internalization so that the pathogen can overcome this barrier by intracellular means.

Receptor for human transferrin: N. meningitides is not able to form 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 enables 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 and thus fever, coagulation disorders and shock. These toxins are toxic cell wall components, such as lipopolysaccharide (LPS), etc. These endotoxins activate macrophages, which release TNF-alpha. This leads to fever, toxic vasculitis, disruption of the coagulation system and bleeding.

IgA proteases: IgA proteases cleave IgA immunoglobulins and inhibit the effect 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 (MAK). This makes efficient C3b-mediated opsonization impossible.

Phase variation and antigen variance: Phase variation, i.e. the switching on and off of certain genes, combined with antigen variance (of surface molecules), plays an important role in the virulence of meningococci. 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). Colonization with non-pathogenic N. lactamica and non-related but immunologically similar bacteria could be important for natural immunity against meningococci.

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 against invasive meningococcal disease, since activated complement leads to the death of the bacteria by direct lysis or by opsonization and phagocytosis.

Individuals who suffer recurrent attacks of Neisseria infections have a high prevalence of familial deficiencies of terminal complement factors (see below primary immunodeficiencies (complement deficiencies). This deficit results in the inability to form the membrane attack 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 will experience a 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 deficiency: Individuals with properdin deficiency, a sex-linked inherited disorder, have functional classical complement activation but impaired alternative activation. More than half of the men in this group develop meningococcal disease, the course of which is often fulminant with a fatal outcome.

Individuals with hypogammaglobulinemia, primary isolated IgM deficiency or functional/organic asplenia also have an increased risk of sporadic meningococcal disease or severe disease progression (see Waterhouse-Friderichsen syndrome below).

The course of a meningococcal infection is acute. The incubation period is 2-5 days. This is followed by the sudden onset of a severe clinical picture with high fever, chills, headache and stiff neck. The bacteremia can lead to an infection of the endothelia with microthrombosis. The release of toxic cell wall components (endotoxins; e.g. lipopolysaccharides) can lead to life-threatening conditions and septic shock. A special clinical feature is the Waterhouse-Friderichsen syndrome with endoxin shock, consumption coagulopathy (purpura fulminans) and hemorrhagic 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 develops 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 the age of 6 to 12 months. It decreases progressively thereafter, presumably due to colonization with closely related, non-pathogenic bacteria such as N. lactamica, avirulent N. meningitidis or other bacteria that express surface antigens that cross-react with those of virulent meningococcal strains.

In some cases, the 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 is not yet clear how meningococci cross the blood-brain barrier (Coureuil M et al. 2019).

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