Also, GAS expresses C5a peptidase to digest C5a and inhibit recruitment of neutrophils to sites of infection ( 22). Unlike M protein, both the hyaluronic acid capsule and collagen recruitment of GAS form the physical barrier on the bacterial surface to avoid complement opsonization and phagocytosis by neutrophils ( 47). The surface M and M-like proteins of GAS avoid opsonization by complement- and phagocytosis-mediated killing, in part by binding to complement regulatory proteins, such as C4b-binding protein, factor H, and factor H-like protein ( 2, 23). Several mechanisms by which GAS evades the innate immunity have been described ( 21, 47). Despite intensive care with antimicrobial therapy, the mortality has remained high for these infections and postinfection sequelae, such as acute rheumatic fever ( 47). Group A streptococcus (GAS Streptococcus pyogenes) is an important human pathogen that causes a variety of infections, including pharyngitis, impetigo, cellulitis, necrotizing fasciitis, puerperal sepsis, and streptococcal toxic shock syndrome ( 11, 41, 42).
These results suggest a novel SPE B mechanism, one which degrades serum C3 and enables GAS to resist complement damage and opsonophagocytosis. A20 opsonized with SPE B-treated serum was more resistant to neutrophil killing than A20 opsonized with normal serum, and SPE B-mediated resistance was C3 dependent. Moreover, the amount of C3 fragments on the A20 cell surface, a SPE B-producing strain, was less than that on its isogenic mutant strain, SW507, after opsonization with normal serum.
SPE B-treated, but not C192S-treated, serum also impaired opsonization of C3 fragments on the surface of GAS strain A20. Reconstitution of C3 into SPE B-treated serum unblocked zymosan-mediated neutrophil activation dose dependently. Further study showed that cleavage of serum C3 by SPE B, but not C192S, blocked zymosan-induced production of reactive oxygen species in neutrophils as a result of decreased deposition of C3 fragments on the zymosan surface. In contrast, C192S, a SPE B mutant lacking protease activity, had no effect on complement activation. Using an enzyme-linked immunosorbent assay, we found that SPE B-treated serum impaired the activation of the classical, the lectin, and the alternative complement pathways. In this study, we examined the mechanism SPE B uses to enable bacteria to resist opsonophagocytosis. The inhibition of phagocytic activity by SPE B may help prevent bacteria from being ingested. Streptococcal pyrogenic exotoxin B (SPE B), a cysteine protease, is an important virulence factor in group A streptococcus (GAS) infection.
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