Variable region in streptococcal M-proteins provides stable binding with host fibrinogen for plasminogen-mediated bacterial invasion

Abstract

Dimeric M-proteins (M-Prt) in group A (GAS) are surface-expressed virulence factors implicated in processes that contribute to the pathogenicity of infection. Sequence analyses of various GAS M-Prts have shown that they contain a highly conserved sortase A-dependent cell wall-anchored C terminus, whereas the surface-exposed N terminus is highly variable, a feature used for identification and serotyping of various GAS strains. This variability also allows for strain-specific responses that suppress host defenses. Previous studies have indeed identified the N-terminal M-Prt B-domain as the site interacting with antiphagocytotic human-host fibrinogen (hFg). Herein, we show that hFg strongly interacts with M-Prts containing highly variable B-domains. We further demonstrate that specific GAS clinical isolates display high affinity for the D-domain of hFg, and this interaction allowed for subsequent surface binding of human-host plasminogen (hPg) to the E-domain of hFg. This GAS surface-bound hPg is then activated by GAS-secreted streptokinase, leading to the generation of an invasive proteolytic bacterial surface. Our results underscore the importance of the human fibrinolytic system in host-pathogen interactions in invasive GAS infections.

Variations in the secondary structures of PAM proteins influence their binding affinities to human plasminogen

“…hPg, diluted to 30 μg/mL in 10 mM sodium acetate, pH 4.5, was injected into flow cell 2 of a CM5 sensor chip. Flow cell 1 was prepared by the same method, but without immobilizing ligands on the chip (Bhattacharya et al, 2014;Chandrahas et al, 2015;Glinton et al, 2017). Ligand immobilizations and binding experiments were performed at various temperatures (15° C, 25° C, 37° C).…”

“…Since M-Prts possess the characteristics to form helical coiled-coils, especially in solution (Glinton et al, 2017;Qiu et al, 2018), it is assumed that dimers are present on the cell surface (Cedervall et al, 1997;Phillips et al, 1981a). However, it is most likely that PAM is translocated through the narrow sortase A secretion (SecA) channel in the cell membrane in an unfolded monomeric state, where the protein is anchored to the pentaglycine residues of the mother and daughter septa of newly forming cell wall and not to previously formed cell wall sites (Raz et al, 2012).…”

Contributions of different modules of the plasminogen-binding Streptococcus pyogenes M-protein that mediate its functional dimerization

“…In addition to direct causation of the infection, GAS has evolved survival mechanisms in different host niches to assist the organism in evasion of the host innate immune response. For example, several Pattern A-C M-Prts interact with hemostasis system proteins, e.g., fibrinogen (Ghosh, 2011; Glinton et al, 2017), to provide fibrin that encapsulates the bacteria to allow their colonization. This serves as an initial protective antiphagocytosis mechanism.…”

The Effect of Permethrin Resistance on Aedes aegypti Transcriptome Following Ingestion of Zika Virus Infected Blood

“…The prophenoloxidase (AAEL011763) is a modified form of the complement response found in insects, and a major innate defense system in invertebrates that controls the melanization of pathogens and damaged tissues [ 52 ]. M protein (AAEL011747), a strongly antiphagocytic and a major virulence factor in viruses, parasites, and bacteria aids in entering by counteracting the mosquito’s defenses [ 53 , 54 ]. In addition, two lachesins, a novel immunoglobulin superfamily protein required for morphogenesis of the Drosophila tracheal system, were also significantly upregulated [ 55 ].…”