Sialic acid of group B Neisseria meningitidis regulates alternative complement pathway activation

Abstract

The effect of meningococcal cell-associated sialic acid on activation of the human alternative complement pathway was examined by using a quantitative fluorescence immunoassay to assess alternative pathway-mediated C3 binding to a group B strain of Neisseria meningitidis from which graded amounts of sialic acid had been removed with neuraminidase. Using human serum absorbed with strain B16B6 (B:2a:L2,3) and chelated with 10 mM MgCl2 and 10 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, we found an increase in the amount of C3 bound by enzymatically desialylated B16B6 organisms over the amount bound by fully sialylated organisms. This increase was proportional to the amount of sialic acid cleaved from the bacteria. Enhanced C3 binding was accompanied by an increase in factor B deposition. A sialic acid-deficient mutant of strain B16B6, designated 2T4-1, bound C3 via the alternative pathway at a level equivalent to that bound by wild-type meningococci from which 88% of the sialic acid had been removed. Strain B16B6 was resistant to the alternative pathway-mediated bactericidal activity of both absorbed and hypogammaglobulinemic human sera, whereas noncapsular variant 2T4-1 was sensitive to these sera. The addition of purified immune immunoglobulin M (IgM) and IgG significantly increased the alternative pathway-mediated killing of strain B16B6 organisms. IgM mediated increased bactericidal activity without an increase in C3 or factor B deposition. In contrast, the IgG-mediated killing was associated with increased binding of C3 and factor B to the organisms. Absorption studies showed that the IgM bound to the sialic acid capsule, whereas the IgG bound to noncapsular surface antigens. We conclude from these results that the group B meningococcal sialic acid capsule inhibits activation of the alternative pathway in the nonimmune host and that both IgM and IgG, although specific for different surface antigens, are capable of augmenting the alternative pathway-mediated killing of group B meningococci.

Masquerading microbial pathogens: capsular polysaccharides mimic host-tissue molecules

“…Early work on the CPS of N. meningitidis serogroup B found that mutants deficient in capsule production lost all pathogenicity in mice (Masson et al, 1982). Several studies have demonstrated that the CPS aids in the resistance of the bacterial cells to the innate immune system (Jarvis & Vedros, 1987;Spinosa et al, 2007). Similar to other CPSs, the PSA capsule of N. meningitidis has been found to hinder adhesion and invasion (Spinosa et al, 2007), and it is unable to activate the complement pathway (Jarvis & Vedros, 1987).…”

“…Several studies have demonstrated that the CPS aids in the resistance of the bacterial cells to the innate immune system (Jarvis & Vedros, 1987;Spinosa et al, 2007). Similar to other CPSs, the PSA capsule of N. meningitidis has been found to hinder adhesion and invasion (Spinosa et al, 2007), and it is unable to activate the complement pathway (Jarvis & Vedros, 1987). This is most likely a result of the capsule masking immunogenic adhesins and invasins on the surface of the bacterial cell.…”

“…This is most likely a result of the capsule masking immunogenic adhesins and invasins on the surface of the bacterial cell. However, it has also been shown that the CPS is vital for the survival of the bacterium in the bloodstream (Jarvis & Vedros, 1987) and important for survival inside human cells (Spinosa et al, 2007). In the bloodstream, the CPS allows N. meningitidis to evade uptake and degradation by macrophages (Jarvis & Vedros, 1987), while intracellularly, the encapsulated bacterial cells are resistant to antimicrobial peptides, which act by binding bacterial membranes and increasing their permeability (Spinosa et al, 2007).…”

The siaA gene involved in capsule polysaccharide biosynthesis of Neisseria meningitidis B codes for N-acylglucosamine-6-phosphate 2-epimerase activity

“…The capsular polysaccharide of N. meningitidis B is considered the major virulence factor of the bacteria. The capsule is composed of a homopolymer of K-(2C8) linked N-acetylneuraminic acid (NeuNAc, sialic acid) and mediates resistance to phagocytosis and lysis by serum complement [1,2]. Four enzymatic steps are needed for sialic acid biosynthesis.…”

Embryonic Neural Cell Adhesion Molecule in Cerebrospinal Fluid of Younger Children: Age‐Dependent Decrease During the First Year

“…Poly-a-2,8-NeuAc has also been identified as a major pathogenicity factor (Cross et al, 1984a) in infectious diseases caused by Escherichia coli KI and Neisseria meningitidis group B because of its low immunogenicity (Wyle et al, 1972) and its highly negative charge, rendering the bacterium resistant to phagocytosis (Jarvis and Vedros, 1987). Attempts to isolate immunological probes for poly-a-2,8-NeuAc resulted in the isolation of several poly-a-2,8-NeuAc-recognizing monoclonal antibodies (MAbs) of the IgM type (Cross et al, 1984a;Kabat et al, 1986;Rougon et al, 1986;Krambowitis et al, 1987), but only one high-titer MAb of the IgG type has been described so far (Frosch et al, 1985).…”