Understanding how leading bacterial pathogens subvert innate immunity to reveal novel therapeutic targets.

Staphylococcus aureus (SA) and group A Streptococcus (GAS) are prominent Gram-positive bacterial pathogens, each associated with a variety of mucosal and invasive human infections. SA and GAS systemic disease reflects diverse abilities of these pathogens to resist clearance by the multifaceted defenses of the human innate immune system. Here we review how SA and GAS avoid the bactericidal activities of cationic antimicrobial peptides, delay phagocyte recruitment, escape neutrophil extracellular traps, inhibit complement and antibody opsonization functions, impair phagocytotic uptake, resist oxidative burst killing, and promote phagocyte lysis or apoptosis. Understanding the molecular basis of SA and GAS innate immune resistance reveals novel therapeutic targets for treatment or prevention of invasive human infections. These future therapies envision alternatives to direct microbial killing, such as blocking disease progression by neutralizing specific virulence factors or boosting key innate immune defenses.