BACKGROUND: Group A Streptococcus (GAS) can cause life-threatening skin infections that progress rapidly and are difficult to treat. Despite all GAS being catalase-negative, neutrophil influx and the subsequent production of ROS is not sufficient to eradicate bacteria from infections occurring in the skin.
METHODS: We used an intradermal infection model in wild-type and gp91phox-/- C57BL/6 mice inoculated with either GAS strain 5448 or an isogenic capsule mutant of 5448 (∆hasA). To evaluate virulence, we measured the size of lesions and enumerated CFU. Susceptibility to hydrogen peroxide was determined by both zone of inhibition and in liquid media by CFU enumeration in the presence of hydrogen peroxide and varying levels of exogenous hyaluronic acid purified from Streptococcus equi.
RESULTS: Bacterial load in lesions was similar in both wild-type and CGD mice, consistent with the finding that ROS does not directly kill GAS in the skin. However, lesions produced by ∆hasA GAS were significantly smaller than those produced by 5448 in wild-type mice. This phenotype was negated in CGD mice since lesions from ∆hasA-infected mice were identical to 5448-infected mice. In vitro, non-encapsulated strains of GAS were significantly more susceptible to hydrogen peroxide, and exogenous hyaluronic acid was sufficient to increase survival of non-encapsulated GAS exposed to hydrogen peroxide. Conversely, hyper-encapsulated strains of GAS were significantly more resistant to peroxide killing.
CONCLUSIONS: Our data propose a mechanism in which the pathology of GAS infection is regulated by ROS production, exposing an avenue of therapeutic benefit. We also propose that hyaluronic acid capsule acts as a direct scavenger of ROS to enhance virulence.