Outcome of a complex interaction

Abstract

Infections caused by Neisseria meningitidis provoke considerable anxiety. Meningococcal disease is transmittable and can affect young and previously healthy people. The course of the disease can be rapid, because meningococci shed large amounts of endotoxin, a constituent of the meningococcal outer membrane that induces fever and shock. Patients can die within hours after the onset of non-specific symptoms, and those who survive often have amputations, hearing loss, and renal failure. Although in Europe only one case arises in every 100 000 inhabitants every year, most individuals are probably colonised by a meningococcal strain at least once a year. Host and bacterial factors regulate the outcome of a complex interaction. The risk of development of disease after nasopharyngeal colonisation is high if protective antibody titres, which vary throughout life, are low at the time of acquisition of a pathogenic strain (figure). The protective antibodies that bind to meningococci are induced by nasopharyngeal colonisation with neisserial species that express cross-reactive antigens. Some individuals are also more susceptible to meningococcal disease because of their genetic makeup. A few patients are at high risk because of deficiencies of complement proteins, which mediate phagocytosis and lyse the bacteria immediately after they enter the bloodstream. Some of these complement deficiencies make the patient susceptible to recurrent episodes of mild meningococcal disease, and others are associated with severe and often lethal forms of the disease. Mutations in the mannose binding lectin, which is also involved in complement activation, enhance susceptibility to the disease. Coagulopathy, an important feature of severe disease, occurs most frequently in patients with polymorphisms in genetic elements that drive the expression of a regulator of the coagulation cascade. The same has been reported for the gene of a cytokine, termed tumour necrosis factor , whose degree of expression correlates with the severity of meningococcal disease. A polysaccharide capsule surrounds pathogenic isolates and prevents phagocytosis and lysis of the bacteria. The chemical composition of the lipopolysaccharide has been identified, as have host cell receptors that interact with meningococci. Researchers are trying to understand how bacteria enter the cerebrospinal fluid. Complete sequencing of the genomes of three genetically different pathogenic meningococcal strains is a driving force in research of meningococcal pathogenicity, because each of the 2100 genes can now be analysed for its contribution. Because of the genetic and antigenetic variability of meningococci, however, we still do not know what cocktail of bacterial factors is sufficient to render a strain dangerous. To answer this question, molecular epidemiologists are studying the distribution of meningococcal lineages in healthy carriers and in patients. Meningococcal sequence types (STs) and their phylogenetic relations are defined by DNA sequence comparisons of housekeeping genes, whose variation is independent of immune selection. Related STs are summarised in meningococcal lineages or complexes. The genetic background of a strain largely determines risk of disease. For example, some meningococcal lineages are frequently found in healthy carriers but never cause disease—ie, the ST-53 complex. Strains of the ST-53 complex are avirulent because they lack capsule synthesis genes. Other lineages also frequently colonise healthy individuals, but can cause meningococcal disease—ie, the ST-22 and ST-23 complexes. These lineages are characterised by expression of the capsular serogroups W-135 and Y, respectively. By contrast, strains of the ST-11 complex are rare in healthy carriers, but cause many instances of serogroup C disease. Therefore, non-immune people who acquire an ST-11 strain are at risk of developing meningitis or severe meningococcal disease. Monitoring such pathogenic lineages is warranted, since new clones are constantly evolving, which can cause meningococcal disease in human populations that lack herd immunity. There are various meningococcal pathogenicity patterns made up of different variants of the capsule, the lipopolysaccharide, outer membrane porins, adhesins, iron-binding proteins, and other unknown virulence factors. This natural variety can be exploited to understand in detail the pathogenicity of N meningitidis, since we now have the tools for the job; molecular epidemiology, human and bacterial genome sequences, and sophisticated pathogenicity research. A human host is colonised by a meningococcal strain The outcome of this interaction is affected by the virulence of the strain, and by the natural immunity and genetic predisposition of the host. Usually an asymptomatic commensal lifestyle of the bacterium results, but sometimes disease occurs.