Abstract
Group A Streptococcus (GAS) is a leading human pathogen producing a diverse array of infections from simple pharyngitis ("strep throat") to invasive conditions, including necrotizing fasciitis and toxic shock syndrome. The surface-anchored GAS M1 protein is a classical virulence factor that promotes phagocyte resistance and exaggerated inflammation by binding host fibrinogen (Fg) to form supramolecular networks. In this study, we used a virulent WT M1T1 GAS strain and its isogenic M1-deficient mutant to examine the role of M1-Fg binding in a proximal step in GAS infection-interaction with the pharyngeal epithelium. Expression of the M1 protein reduced GAS adherence to human pharyngeal keratinocytes by 2-fold, and this difference was increased to 4-fold in the presence of Fg. In stationary phase, surface M1 protein cleavage by the GAS cysteine protease SpeB eliminated Fg binding and relieved its inhibitory effect on GAS pharyngeal cell adherence. In a mouse model of GAS colonization of nasal-associated lymphoid tissue, M1 protein expression was associated with an average 6-fold decreased GAS recovery in isogenic strain competition assays. Thus, GAS M1 protein-Fg binding reduces GAS pharyngeal cell adherence and colonization in a fashion that is counterbalanced by SpeB. Inactivation of SpeB during the shift to invasive GAS disease allows M1-Fg binding, increasing pathogen phagocyte resistance and proinflammatory activities.
Highlights
The group A Streptococcus (GAS) M1 protein binds fibrinogen (Fg) to block phagocytosis and to form a proinflammatory complex
As a first step in our analysis, we tested the contribution of the M1 protein to Fg binding by WT M1T1 GAS strain 5448, representative of the contemporary hypervirulent clone associated with pharyngitis and invasive infections worldwide
We have shown that the M1 protein is the major Fg-binding protein for the globally disseminated M1T1 GAS clone and is sufficient to promote Fg binding when heterologously expressed in a nonpathogenic Gram-positive bacterium
Summary
The group A Streptococcus (GAS) M1 protein binds fibrinogen (Fg) to block phagocytosis and to form a proinflammatory complex. The up-regulated genes include the operon for synthesis of the hyaluronic acid capsule and the genes encoding streptolysin O, NAD glycohydrolase, the interleukin-8 protease SpyCEP/ScpC, and the DNase Sda1 These mutations in the covRS operon abolish expression of streptococcal pyrogenic exotoxin B (SpeB), a broad-spectrum, secreted cysteine protease [19] that can degrade several GAS extracellular proteins and virulence factors [20]. This function may depend on the M serotype and target cell; for example, M6 and M24 proteins mediate adherence of GAS to human soft palate, whereas M18 does not [32] These considerations led us to study how the M1 protein (and in particular, its ability to bind Fg) influences pharyngeal epithelial interactions during early GAS infection
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