Abstract

Evasion of complement-mediated opsonophagocytosis enables group A Streptococcus pyogenes (GAS) to establish infection. Different strain-dependent mechanisms are employed by the host to accomplish this goal. In general, GAS inhibits the amplification of the complement cascade on its cell surface by facilitating the degradation of C3b, an opsonin, to an inactive product, inactivated C3b (iC3b), in a step catalyzed by factor I (FI) and its cofactor, factor H (FH), with or without the participation of human host plasmin (hPm). GAS recruits FH to its cell surface via FH receptors, which are transcriptionally controlled by the two-component cluster of virulence responder-sensor system. The manner in which FI-FH and hPm function together on GAS cells is unknown. Using GAS strain AP53, which strongly binds host human plasminogen/plasmin (hPg/hPm) directly via an hPg/hPm surface receptor (PAM), we show that both FI-FH and hPm sequentially cleave C3b. Whereas FI-FH proteolytically cleaves C3b into iC3b, PAM-bound hPm catalyzes cleavage of iC3b into multiple smaller peptides. Unlike AP53, GAS strain M23ND weakly binds FH and recruits hPg/hPm to its cell surface indirectly via fibrinogen bound to M-protein, M23. In this case, FH-FI cleaves C3b into iC3b, with negligible degradation of iC3b by hPm that is bound to fibrinogen on the cells. AP53 and M23ND display similar resistance to human neutrophil-mediated phagocytosis, which results in a corresponding high lethality in mice after injection of these cells. These results suggest that GAS utilizes diverse mechanisms to degrade C3b and thus to protect bacterial cells from the complement response of the host.

Highlights

  • With diverse clinical manifestations, with high specificity for humans

  • We examined the inactivation of C3b by the factor H (FH)-factor I (FI) complex and by host plasmin (hPm), along with their effects on phagocytosis, and the consequent lethality in mice using group A Streptococcus pyogenes (GAS) strains AP53 and M23ND

  • FH Binding to GAS Strains—To determine how C3b is cleaved on the surface of different GAS strains, we chose two different strains, AP53 and M23ND, because of important differences in the mode of generation of hPm

Read more

Summary

Introduction

With diverse clinical manifestations, with high specificity for humans. GAS can cause common illnesses, such as impetigo, pharyngitis, and scarlet fever, and can cause life-threatening sequelae, such as necrotizing fasciitis, streptococcal toxic shock syndrome, and acute post-streptococcal glomerulonephritis [1, 2]. A second hypervirulent GAS strain was used that expresses the emm23 subtype that activates hPg to hPm rapidly only in the presence of the direct hFg-binding M-protein, M23 [28] (Fig. 1B).

Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call