title: 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.
authors.affiliation: From the W.M. Keck Center for Transgene Research and the Departments of Chemistry and Biochemistry and.
authors.forename: Garima
authors.initials: G
authors.lastname: Agrahari
authors.affiliation: From the W.M. Keck Center for Transgene Research and the Departments of Chemistry and Biochemistry and.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Liang
authors.affiliation: From the W.M. Keck Center for Transgene Research and the Departments of Chemistry and Biochemistry and.
authors.forename: Kristofor
authors.initials: K
authors.lastname: Glinton
authors.affiliation: From the W.M. Keck Center for Transgene Research and Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556.
authors.forename: Shaun W
authors.initials: SW
authors.lastname: Lee
authors.affiliation: From the W.M. Keck Center for Transgene Research and the Departments of Chemistry and Biochemistry and.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Ploplis
authors.affiliation: From the W.M. Keck Center for Transgene Research and the Departments of Chemistry and Biochemistry and fcastell@nd.edu.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D003179:Complement C3b / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D010587:Phagocytosis; D013045:Species Specificity; D013290:Streptococcal Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013297:Streptococcus pyogenes / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; C084529:plasminogen-binding protein, bacteria; D003179:Complement C3b
keywords: Gram-positive bacteria; bacteria; bacterial pathogenesis; complement; complement system; immunology; innate immunity