Chapter 136. Meningococcal Infections (Part 3)

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Outer-Membrane Components Associated with Virulence Meningococcal 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) Outer-Membrane Components Associated with Virulence Meningococcal 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, or 29E capsular serogroups. Capsules impart antiphagocytic and antibactericidal
properties to the meningococcus and thus enhance meningococcal survival during invasion 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 survival externally and within intracellular compartments such as phagocytic vacuoles. Except in serogroup A, the major meningococcal capsular polysaccharides associated with invasive disease are composed of polymers of sialic acid (N-acetyl neuraminic acid, NANA) derivatives. The serogroup B capsule is composed of (α2→8)-linked NANA, the serogroup C capsule of (α-2Æ9)-linked NANA, the serogroup Y capsule of alternating D-glucose and NANA, and the serogroup W- 135 capsule of D-galactose and NANA. The differences in sialic acid capsule composition are derived from the distinct polysialyltransferases encoded by the fourth gene of the capsule biosynthesis operon, which is also used as a basis for capsule-specific PCR diagnosis. A four-gene operon encoding the capsule transport apparatus (ctr) is conserved among different serogroups and is also used in 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-gene biosynthesis cassette unique for this serogroup. Outer-Membrane Proteins
Meningococci isolated from sites of colonization or invasive disease are piliated. Pili are complex outer-membrane, protein-based organelles that facilitate adhesion—the first step in meningococcal–host cell interactions. Meningococci express two major OMP porins, PorA and PorB. Human opsonins and bactericidal antibodies induced during meningococcal disease have been shown to recognize PorA and PorB. Vaccines based on PorA-containing outer-membrane vesicles are under development. Another OMP, Opc, is involved in cell attachment and is also a target of bactericidal antibodies. Meningococci encounter iron-restricted environments during infection. The majority of host iron is presented intracellularly as hemoglobin and extracellularly as human transferrin and lactoferrin. 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 repeating O-antigen subunits of sugars. The lipid A moiety of LOS, which has been classically termed endotoxin (as opposed to the bacterial exotoxins), is the portion that mediates the induction of inflammatory cytokines often seen in disease. The effect of lipid A is due to an interaction with the innate immune receptor Toll-like receptor 4 (TLR4) in association with the membrane protein MD2. TLR4 and
MD2 are found mainly on macrophages/monocytes, dendritic cells, and other phagocytes. Rates of morbidity and mortality associated with meningococcal bacteremia and meningitis have been directly correlated with the amount of circulating meningococcal endotoxin. Whether this measure is an indication of overall bacterial load or is a direct pathogenic mechanism of disease is debatable. The ability of signaling through TLR4 by the lipid A moiety of LOS to induce production of inflammatory and proinflammatory cytokines from various immune cells suggests a direct relationship. However, other meningococcal outer- membrane components—e.g., meningococcal porins and lipoproteins (including the H8 lipoprotein)—induce immune cell activation via other TLRs, especially TLR2. A recently derived LOS– meningococcal mutant was still able to induce significant production of proinflammatory cytokines [especially tumor necrosis factor α (TNF-α), interleukin (IL) 6, and IL-1β] by macrophages and cytokines. This observation suggests a potential role for these components in induction of meningococcal sepsis. Other Virulence Mechanisms The outer-membrane components of N. meningitidis (e.g., pili, LOS, Opa proteins, Opc, capsule) vary in expression or structure at high frequencies (10 –2– 10–4 per cell per generation). Variation is the result of genetic switches that turn
expression of a component on or off, regulate the amount of a component, or alter the structure of a component. Genetic events leading to phase and structural variation allow immune escape and create variability in the structures that are important in pathogenesis (on and off expression of attachment ligands, protection against serum killing, invasion determinants). The serogroup B capsule provides an example of how meningococci downregulate the human immune response through the expression of host-like antigens. The (α2→8)-linked polysialic acid capsule of serogroup B meningococci is identical to structures on the human neural cell adhesion molecule N-CAM. Meningococci are also characterized by frequent vesiculation (blebbing) of the outer membrane, and the amount of blebbing may vary between strains. Blebs may contribute to the rapid initiation of the inflammatory and clotting cascades. They may also be related to the natural autolysis of meningococci that results in DNA release and facilitates genetic transformation.