Streptococcus pyogenes, or Group A Streptococcus (GAS), is a human opportunistic pathogen that is responsible for a number of diseases ranging from skin and soft tissue infections, such as pharyngitis to severe invasive diseases such as streptococcal toxic shock syndrome. Untreated pharyngitis can also develop into acute rheumatic fever (ARF) and rheumatic heart disease (RHD), a major cause of acquired heart disease in the developing world, in particular of school-aged children (1). Using bioinformatic analysis of the GAS SF370 strain (serotype M1) genome, we have identified a novel GAS virulence factor, which we believe facilitates bacterial immune evasion. The protein was predicted to possess 5’-nucleotidase activity, which allows conversion of nucleotide-monophosphates into nucleosides and was therefore named streptococcal 5’-nucleosidase A (S5nA). Adenosine is an important immune modulator that decreases the phagocytic activity of macrophages by suppressing the generation of nitric oxide, superoxide and pro-inflammatory cytokines (2). In addition, adenosine inhibits neutrophil degranulation. We have generated recombinant soluble S5nA and confirmed its predicted enzymatic activity. Recombinant S5nA converted AMP and ADP (but not ATP) into adenosine. In addition, rS5nA converted dAMP into deoxy-adenosine (dAdo), a molecule that induces apoptotic killing of macrophages and monocytes (3). We have previously shown that the extracellular Streptococcus pyogenes nuclease A (SpnA) destroys neutrophil extracellular traps (NETs) by degrading the backbone DNA structure (4). NETs are produced by neutrophils during infection and are able to trap and kill bacteria. We believe that S5nA and SpnA work synergistically by destroying NETs and kill macrophages by using the NET breakdown product dAMP to generate dAdo.