Streptococcus pyogenes Employs Strain-dependent Mechanisms of C3b Inactivation to Inhibit Phagocytosis and Killing of Bacteria

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.

CovR Regulates Streptococcus mutans Susceptibility To Complement Immunity and Survival in Blood

“…In GAS, natural mu- tations in covR Spy were detected in strains involved in human infections, and inactivation of the CovRS Spy TCS enhanced strain virulence in murine models (48)(49)(50). Virulence genes repressed by CovR Spy include genes involved in complement evasion (e.g., has operon for hyaluronic acid capsule synthesis) (50)(51)(52), which are not present in S. mutans genomes (53,54). Reduced transcript levels of covR Sm in blood isolates associated with increased transcription of CovR Sm -repressed genes (gbpC, gbpB, and epsC) suggest that the diversity in covR Sm activities influences the capacities of S. mutans strains to survive in the bloodstream.…”

Complement factor H family proteins in their non-canonical role as modulators of cellular functions

“…[97][98][99][100][101][102]. On one hand, pathogens can avoid complement attack and opsonophagocytosis by recruiting factor H on their surface [97,[103][104][105][106][107]. On the other hand, factor H can enhance adhesion of the pathogen to phagocytes by binding to specific receptors [62,63].…”

Conformationally organized lysine isosteres in Streptococcus pyogenes M protein mediate direct high-affinity binding to human plasminogen

“…Important among these properties is the fibrinolytic system, which GAS employs to potently evade innate immunity (e.g. attenuate complement-based opsonization of GAS) (10,11) and to disseminate into deep tissue. To accomplish this function, PAM first interacts with very high affinity to host human plasma plasminogen (hPg) (12), a step that facilitates its activation to plasmin by GAS-secreted streptokinase (13,14).…”