Wall teichoic acid (WTA) of Staphylococcus aureus is a major cell envelope-associated glycopolymer that is a key molecule in promoting colonization during S. aureus infection. The complement system plays a key role in the opsonization and clearance of pathogens. We recently reported that S. aureus WTA functions as a ligand of human serum mannose-binding lectin (MBL), a recognition molecule of the lectin complement pathway. Intriguingly, serum MBL in adults does not bind to WTA because of an inhibitory effect of serum anti–WTA-IgG. In this study, serum anti–WTA-IgG was purified to homogeneity using a purified S. aureus WTA-coupled affinity column to examine the biological function of human anti–WTA-IgG. The purified anti–WTA-IgG contained the IgG2 subclass as a major component and specifically induced C4 and C3 deposition on the S. aureus surface in the anti–WTA-IgG–depleted serum, but not in C1q-deficient serum. Furthermore, the anti–WTA-IgG–dependent C3 deposition induced phagocytosis of S. aureus cells by human polymorphonuclear leukocytes. These results demonstrate that serum anti–WTA-IgG is a real trigger for the induction of classical complement-dependent opsonophagocytosis against S. aureus. Our results also support the fact that a lack of the lectin complement pathway in MBL-deficient adults is compensated by Ag-specific, Ab-mediated adaptive immunity.
Serotype III group B streptococci (GBS) are a common cause of neonatal sepsis and meningitis. Although deficiency in maternal capsular polysaccharide (CPS)-specific IgG correlates with susceptibility of neonates to the GBS infection, serum deficient in CPS-specific IgG mediates significant opsonophagocytosis. This IgG-independent opsonophagocytosis requires activation of the complement pathway, a process requiring the presence of both Ca2+ and Mg2+, and is significantly reduced by chelating Ca2+ with EGTA. In these studies, we defined a role of L-ficolin/mannose-binding lectin-associated serine protease (MASP) complexes in Ca2+-dependent, Ab-independent opsonophagocytosis of serotype III GBS. Incubation of GBS with affinity-purified L-ficolin/MASP complexes and C1q-depleted serum deficient in CPS-specific Ab supported opsonophagocytic killing, and this killing was inhibited by fluid-phase N-acetylglucosamine, the ligand for L-ficolin. Binding of L-ficolin was proportional to the CPS content of individual strains, and opsonophagocytic killing and C4 activation were inhibited by fluid-phase CPS, suggesting that L-ficolin binds to CPS. Sialic acid is known to inhibit alternative complement pathway activation, and, as expected, the bactericidal index (percentage of bacteria killed) for individual strains was inversely proportional to the sialic acid content of the CPS, and L-ficolin-initiated opsonophagocytic killing was significantly increased by addition of CPS-specific IgG2, which increased activation of the alternative pathway. We conclude that binding of L-ficolin/MASP complexes to the CPS generates C3 convertase C4b2a, which deposits C3b on GBS. C3b deposited by this lectin pathway forms alternative pathway C3 convertase C3bBb whose activity is enhanced by CPS-specific IgG2, leading to increased opsonophagocytic killing by further deposition of C3b on the GBS.
Phylogenetic lineages of pathogenic Streptococcus agalactiae (group B streptococci [GBS]) can be identified by analysis of restriction-digestion patterns (RDPs) of chromosomal DNA. The purpose of the present study was to correlate GBS RDP types and (1) alleles of the highly conserved gene encoding translation-initiation factor IF2, infB, and/or (2) the inserted elements IS1548 and GBSi1. Only 1 combination of serotype and infB allele was found within each RDP type. Strains within a particular RDP type also tend to have the same inserted elements in each of 3 loci examined. A novel insertion sequence, designated "IS1563," was found within all RDP type II-2 strains. Most RDP types could be identified by a combination of serotype, infB allele, and inserted elements at each of the loci. These molecular markers can be used to identify GBS populations and to correlate RDP types and phylogenetic lineages identified by different methods.
Group B streptococci (GBS) are the most common cause of neonatal sepsis and meningitis. Most infants who are colonized with GBS at birth do not develop invasive disease, although many of these uninfected infants lack protective levels of capsular polysaccharide (CPS)-specific antibody. The lectin pathway of complement is a potential mechanism for initiating opsonization of GBS with CPS-specific antibody-deficient serum. In this study, we determined whether mannose-binding lectin (MBL)/MBL-associated serine protease (MASP) complexes and L-ficolin/MASP complexes bind to different strains of GBS to activate the lectin pathway, and we identified the molecules recognized by lectins on the GBS surface. We found that MBL did not bind to any GBS examined, whereas L-ficolin bound to GBS cells of many serotypes. L-ficolin binding to GBS cells correlated with the CPS content in serotypes Ib, III (restriction digestion pattern types III-2 and III-3), and V but not with the group B-specific polysaccharide (GBPS) content or with the lipoteichoic acid (LTA) content. L-ficolin bound to purified CPS and GBPS in a concentration-dependent manner but not to purified LTA. All strains to which L-ficolin/MASP complexes bound consumed C4. When N-acetylneuraminic acid (NeuNAc) was selectively removed from GBS cells by treatment with neuraminidase, the reduction in L-ficolin binding was correlated with the amount of NeuNAc removed. Additionally, L-ficolin was able to bind to wild-type strains but was able to bind only weakly to unencapsulated mutants and a mutant strain in which the CPS lacks NeuNAc. We concluded that L-ficolin/MASP complexes bind to GBS primarily through an interaction with NeuNAc of CPS.
Group B streptococci (GBS) are an important cause of serious bacterial disease in neonates, pregnant women, and adults with underlying illnesses (2). GBS are subclassified into serotypes according to the immunologic reactivity of the polysaccharide capsule. Of the nine serotypes, types I, II, III, and more recently, types V and VIII GBS cause the majority of neonatal human GBS disease (2,4,12). Serotype III GBS are particularly important because type III GBS cause a significant percentage of early-onset disease (within the first week of life) and the majority of late-onset disease (after the first week of life) in human neonates and also cause the vast majority of neonatal GBS meningitis cases (2).We previously showed that serotype III GBS can be subclassified by computer-assisted numerical analysis of restriction digest patterns (RDPs) of chromosomal DNA (14). In a more recent study, we showed that serotype III GBS isolated from Tokyo, Japan, and Salt Lake City, Utah, can be classified into three major RDP types, III-1, III-2, and III-3, according to the similarity of the HindIII RDPs (16). The III-2 and III-3 strains can be further subdivided into III-2a and III-2b and III-3a and III-3b, respectively, based on the similarity of the Sse83871 RDPs. The overwhelming majority (91%) of invasive isolates obtained from neonates in that study were III-3 (III-3a or III-3b), whereas only 33% of vaginal isolates were III-3, thereby implying that III-3 strains are more invasive than the other RDP types (16).The reason for the increased pathogenicity of the III-3 strains is not understood. Resistance to opsonization by complement is the major bacterial virulence factor that has been identified to contribute to invasive GBS disease in human neonates. Resistance of serotype III GBS to opsonophagocytosis is proportional to the sialic acid content of the capsular polysaccharide, since removal of sialic acid by treatment with neuraminidase, or by transposon-insertional mutagenesis, increases deposition of opsonic C3 fragments (C3b and C3bi) by allowing activation of the alternative pathway of complement (8,13). The mean capsular sialic content of III-3 strains is significantly higher than that of either III-2 or III-1 strains, suggesting that increased virulence of III-3 strains is at least partly due to the high sialic acid content of their capsules (16).We previously proposed that the bacterial enzyme C5a-ase contributes to the pathogenicity of GBS by the ability of C5aase to rapidly inactivate the potent complement-derived polymorphonuclear leukocyte (PMN) agonist C5a (5, 11), thereby reducing PMN recruitment to sites of inflammation (6) and C5a-mediated stimulation of PMN phagocytosis (17). We therefore expected that invasive type III GBS would uniformly express C5a-ase. Indeed, 96% of III-3a strains express C5a-ase, but none of the III-3b strains express C5a-ase, despite the fact that III-3b strains cause a significant proportion of type III GBS invasive disease. These results suggest that C5a-ase is not critical for all II...
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