Plasmin(ogen) Acquisition by Group A <b><i>Streptococcus</i></b> Protects against C3b-Mediated Neutrophil Killing

Abstract

The globally significant human pathogen group A Streptococcus (GAS) sequesters the host protease plasmin to the cell surface during invasive disease initiation. Recent evidence has shown that localized plasmin activity prevents opsonization of several bacterial species by key components of the innate immune system in vitro. Here we demonstrate that plasmin at the GAS cell surface resulted in degradation of complement factor C3b, and that plasminogen acquisition is associated with a decrease in C3b opsonization and neutrophil-mediated killing in vitro. Furthermore, the ability to acquire cell surface plasmin(ogen) correlates directly with a decrease in C3b opsonization, neutrophil phagocytosis, and increased bacterial survival in a humanized plasminogen mouse model of infection. These findings demonstrate that localized plasmin(ogen) plays an important role in facilitating GAS escape from the host innate immune response and increases bacterial virulence in the early stages of infection.

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

“…M-protein-and Mrp-mediated (182) fibrinogen binding confers resistance to phagocytosis by preventing complement C3 convertase deposition on the bacterial surface (183)(184)(185). Similarly, M-protein-mediated plasminogen binding prevents deposition of the opsonin C3b, preventing phagocytic uptake of GAS by neutrophils (186). Furthermore, the M protein impairs phagosome maturation by inhibiting the fusion of azurophilic granules within the phagosome (187).…”

<b><i>Streptococcus pyogenes</i></b> Escapes Killing from Extracellular Histones through Plasminogen Binding and Activation by Streptokinase

“…This assumption is underlined by reports of Hollands et al [41 ]and Ly et al [42], describing that plasminogen acquisition protects S. pyogenes from killing by other antimicrobials, such as cathelicidin LL-37 and complement factor C3b.…”

Catch Me if You Can: <b><i>Streptococcus pyogenes</i></b> Complement Evasion Strategies

“…1 (1)) [12, 13]. Furthermore, and probably as important, these virulence factors can bind a broad variety of host proteins, namely C4BP and FH, fibrinogen, fibrin, plasmin(-ogen), neural-cell adhesion molecule (NCAM), and different immunoglobulins [14-17]. …”

“…S. pyogenes binds and recruits plasminogen directly at the cell surface, which subsequently becomes activated by the host activators urokinase and tissue plasminogen activator. Interestingly, it has been shown that to protect against C3b-mediated phagocytosis, the accumulation of plasminogen to the bacterial surface (and not plasmin) was the critical factor [17]. Although streptokinase (Fig.…”