Chapter 136. Meningococcal Infections (Part 3)

Outer-Membrane Components Associated with VirulenceMeningococcal strains are characterized by the expression of capsular polysaccharide and other outer-membrane structures, including LOS (endotoxin). Outer-membrane blebbing, meningococcal autolysis, molecular mimicry, genome plasticity, horizontal DNA exchange, and phase and/or antigenic variation are all important in meningococcal virulence.Capsule The polysaccharide capsule is a major—if not the major—virulence factor of N. meningitidis. As stated above, meningococci isolated from the blood or cerebrospinal fluid (CSF) of patients with invasive meningococcal disease most often express capsules of serogroups A, B, C, Y, and W-135. Isolates from asymptomatic nasopharyngeal carriers are nongroupable or express B, Y, X, Z,...
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Chapter 136. Meningococcal Infections (Part 3) Chapter 136. Meningococcal Infections (Part 3) Outer-Membrane Components Associated with Virulence Meningococcal strains are characterized by the expression of capsularpolysaccharide and other outer-membrane structures, including LOS (endotoxin).Outer-membrane blebbing, meningococcal autolysis, molecular mimicry, genomeplasticity, horizontal DNA exchange, and phase and/or antigenic variation are allimportant in meningococcal virulence. Capsule The polysaccharide capsule is a major—if not the major—virulence factorof N. meningitidis. As stated above, meningococci isolated from the blood orcerebrospinal fluid (CSF) of patients with invasive meningococcal disease mostoften express capsules of serogroups A, B, C, Y, and W-135. Isolates fromasymptomatic nasopharyngeal carriers are nongroupable or express B, Y, X, Z, or29E capsular serogroups. Capsules impart antiphagocytic and antibactericidalproperties to the meningococcus and thus enhance meningococcal survival duringinvasion of the bloodstream or CSF. Capsules also provide protective properties(e.g., preventing desiccation and phagocytic killing) and antiadherent properties;these properties promote meningococcal transmission, spread, and survivalexternally and within intracellular compartments such as phagocytic vacuoles. Except in serogroup A, the major meningococcal capsular polysaccharidesassociated with invasive disease are composed of polymers of sialic acid (N-acetylneuraminic acid, NANA) derivatives. The serogroup B capsule is composed of(α2→8)-linked NANA, the serogroup C capsule of (α-2Æ9)-linked NANA, theserogroup Y capsule of alternating D-glucose and NANA, and the serogroup W-135 capsule of D-galactose and NANA. The differences in sialic acid capsulecomposition are derived from the distinct polysialyltransferases encoded by thefourth gene of the capsule biosynthesis operon, which is also used as a basis forcapsule-specific PCR diagnosis. A four-gene operon encoding the capsuletransport apparatus (ctr) is conserved among different serogroups and is also usedin PCR diagnosis. The serogroup A capsule is composed of repeating units of (α)-linked N-acetyl-mannosamine-1-phosphate and is encoded by a four-genebiosynthesis cassette unique for this serogroup. Outer-Membrane Proteins Meningococci isolated from sites of colonization or invasive disease arepiliated. Pili are complex outer-membrane, protein-based organelles that facilitateadhesion—the first step in meningococcal–host cell interactions. Meningococciexpress two major OMP porins, PorA and PorB. Human opsonins and bactericidalantibodies induced during meningococcal disease have been shown to recognizePorA and PorB. Vaccines based on PorA-containing outer-membrane vesicles areunder development. Another OMP, Opc, is involved in cell attachment and is alsoa target of bactericidal antibodies. Meningococci encounter iron-restrictedenvironments during infection. The majority of host iron is presentedintracellularly as hemoglobin and extracellularly as human transferrin andlactoferrin. Meningococci have evolved systems for acquisition of these iron-carrying molecules. Lipooligosaccharide Meningococcal LOS is structurally related to the lipopolysaccharide (LPS)expressed by many gram-negative bacilli. However, LOS does not have repeatingO-antigen subunits of sugars. The lipid A moiety of LOS, which has beenclassically termed endotoxin (as opposed to the bacterial exotoxins), is the portionthat mediates the induction of inflammatory cytokines often seen in disease. Theeffect of lipid A is due to an interaction with the innate immune receptor Toll-likereceptor 4 (TLR4) in association with the membrane protein MD2. TLR4 andMD2 are found mainly on macrophages/monocytes, dendritic cells, and otherphagocytes. Rates of morbidity and mortality associated with meningococcal bacteremiaand meningitis have been directly correlated with the amount of circulatingmeningococcal endotoxin. Whether this measure is an indication of overallbacterial load or is a direct pathogenic mechanism of disease is debatable. Theability of signaling through TLR4 by the lipid A moiety of LOS to induceproduction of inflammatory and proinflammatory cytokines from various immunecells suggests a direct relationship. However, other meningococcal outer-membrane components—e.g., meningococcal porins and lipoproteins (includingthe H8 lipoprotein)—induce immune cell activation via other TLRs, especiallyTLR2. A recently derived LOS– meningococcal mutant was still able to inducesignificant production of proinflammatory cytokines [especially tumor necrosisfactor α (TNF-α), interleukin (IL) 6, and IL-1β] by macrophages and cytoki ...