The M1 Protein of <b><i>Streptococcus pyogenes</i></b> Triggers an Innate Uptake Mechanism into Polarized Human Endothelial Cells

Abstract

Serotype M1 Streptococcus pyogenes is a major human pathogen associated with severe invasive diseases causing high morbidity and mortality. In a substantial number of cases, invasive disease develops in previously healthy individuals with no obvious port of entry. This has led to the hypothesis that the source of streptococci in these cases is a transient bacteraemia. This study focuses on the analysis of interaction of tissue-invasive serotype M1 S. pyogenes with human endothelial cells (EC) of the vascular system. We identify the M1 surface protein of S. pyogenes as the EC invasin which is recognised by polarized human blood EC, thereby triggering rapid, phagocytosis-like uptake of streptococci into polarized EC layers. Upon internalization, the M1 S. pyogenes serotype is incorporated into phagosomes which traffic via the endosomal/lysosomal pathway. However, some of the streptococci successfully evade this innate killing process and hereby mediate their escape into the cytoplasm of the host cell. The results of this study demonstrate that blood EC possess an efficient uptake mechanism for serotype M1 S. pyogenes. Despite efficient phagocytosis, streptococcal survival within EC constitutes one potential mechanism which favours intracellular persistence and thus facilitates continuous infection and dissemination from the primary side of infection into deep tissue.

Vigilant Keratinocytes Trigger Pathogen-Associated Molecular Pattern Signaling in Response to Streptococcal M1 Protein

“…Streptococcal M and M-like proteins are important virulence determinants that interact not only with cell types such as neutrophils, monocytes, and endothelial cells but also with keratinocytes (16,(37)(38)(39), which were the focus of this study. It was already described in 1995 that M and M-like proteins are responsible for bacterial adherence to keratinocytes by binding to membrane cofactor protein (CD46) (39).…”

Immunization with a streptococcal multiple-epitope recombinant protein protects mice against invasive group A streptococcal infection

“…M protein consists of an N-terminal variable domain and a conserved C-terminal domain. Expression of M protein on the bacterial surface is important for GAS virulence, as this mediates the adhesion and internalization of GAS into host cells [13–16]. The N-terminal domain of M protein can bind to serum complement regulator C4b-binding protein (C4BP), which helps GAS avoid phagocytic killing by interfering with host complement activation [17].…”

A Farewell to Arms: Streptococcal Strategies to Cope with Innate Immunity

“…This has led to the hypothesis that streptococci have to cause a transient bacteremia that facilitates their dissemination within the host's body. In this issue of the Journal of Innate Immunity , Ochel et al [2] show that S. pyogenes of the M1 serotype can invade endothelial cells. The study focuses on the tissue-invasive serotype M1 of S. pyogenes , demonstrating that the pathogen can enter the endothelial cells of blood vessels, thereby escaping host defense, and can survive in the cytoplasm of these cells.…”

“…Upon internalization in endothelial cells, the M1 S. pyogenes serotype is incorporated into phagosomes that traffic via the endosomal/lysosomal pathway [2] . Intracellular killing in nonprofessional phagocytes may also include other mechanisms, for example perforin-like molecules, as seen in fibroblasts [10] .…”

“…Intracellular killing in nonprofessional phagocytes may also include other mechanisms, for example perforin-like molecules, as seen in fibroblasts [10] . However, in endothelial cells, some of the streptococci successfully evade this innate killing process and escape into the cytoplasm of the host cell [2] . In macrophages, the intracellular pattern-recognition receptor TLR9 (Toll-like receptor 9) promotes macrophage hypoxia-inducible factor-1α levels, oxidative burst and nitric oxide production in response to group A Streptococcus .…”