Streptococcus pyogenes biofilms-formation, biology, and clinical relevance

Abstract

Streptococcus pyogenes (group A streptococci, GAS) is an exclusive human bacterial pathogen. The virulence potential of this species is tremendous. Interactions with humans range from asymptomatic carriage over mild and superficial infections of skin and mucosal membranes up to systemic purulent toxic-invasive disease manifestations. Particularly the latter are a severe threat for predisposed patients and lead to significant death tolls worldwide. This places GAS among the most important Gram-positive bacterial pathogens. Many recent reviews have highlighted the GAS repertoire of virulence factors, regulators and regulatory circuits/networks that enable GAS to colonize the host and to deal with all levels of the host immune defense. This covers in vitro and in vivo studies, including animal infection studies based on mice and more relevant, macaque monkeys. It is now appreciated that GAS, like many other bacterial species, do not necessarily exclusively live in a planktonic lifestyle. GAS is capable of microcolony and biofilm formation on host cells and tissues. We are now beginning to understand that this feature significantly contributes to GAS pathogenesis. In this review we will discuss the current knowledge on GAS biofilm formation, the biofilm-phenotype associated virulence factors, regulatory aspects of biofilm formation, the clinical relevance, and finally contemporary treatment regimens and future treatment options.

Keywords: S. pyogenes; antibiotic resistance; biofilm; transcriptional regulation; virulence factors.

Figure 1

Three-dimensional images of biofilms of various GAS emm/FCT types grown in C-medium in the absence or presence of glucose. Cells were stained with Alexa Fluor 647 and visualized via Confocal Laser Scanning Microscopy (CLSM); magnification 600 times; box size 13.8 × 13.8 μm. Left panel: non-supplemented C-medium. Right panel: C-Medium supplemented with 30 mM glucose. Strain names, emm-types, and FCT types are given in the middle column.

Figure 2

Regulatory network involved in GAS biofilm formation. Arrow heads indicate direct or indirect induction, blocked lines indicate direct or indirect repression, dashed lines indicate export out of the bacterial cell, and dotted lines indicate ambiguous effects. Outer circle (light blue): transcriptional regulation level; Inner circle (darker blue): biofilm-associated virulence factors; Outside: environmental conditions and quorum sensing peptides influencing the biofilm phenotype. “?” stands for unknown Regulator/regulatory mechanism.

Figure 3

Confocal Laser Scanning micrographs of 24 h emm3/FCT-3 GAS strain HRO-K-044 biofilms cultured in alkalined or acidified C-medium. Cells were stained with live/dead dye containing Syto9 and Propidiumiodide. Magnification 630 times; box size: 19.8 × 19.8 μm. Left panel: mature biofilm grown in C-medium with initial pH of 8.5. Right panel: mature biofilm grown in C-medium with initial pH of 6.5. Upper row: 45° perspective. Lower row: top view.