Streptococcus pyogenes is a significant human pathogen that can cause life-threatening invasive infections. Understanding the mechanism of disease is crucial to the development of more effective therapies. In this report, we explored the role of PGE(2), an arachidonic acid metabolite, and its rate-limiting enzyme cyclooxygenase 2 (COX-2) in the pathogenesis of severe S. pyogenes infections. We found that the COX-2 expression levels in tissue biopsies from S. pyogenes-infected patients, as well as in tissue of experimentally infected mice, strongly correlated with the severity of infection. This harmful effect was attributed to PGE(2)-mediated suppression of the bactericidial activity of macrophages through interaction with the G2-coupled E prostanoid receptor. The suppressive effect of PGE(2) was associated with enhanced intracellular cAMP production and was mimicked by the cAMP-elevating agent, forskolin. Activation of protein kinase A (PKA) was the downstream effector mechanisms of cAMP because treatment with PKI(14-22), a highly specific inhibitor of PKA, prevented the PGE(2)-mediated inhibition of S. pyogenes killing in macrophages. The inhibitory effect exerted by PKA in the generation of antimicrobial oxygen radical species seems to be the ultimate effector mechanism responsible for the PGE(2)-mediated downregulation of the macrophage bactericidal activity. Importantly, either genetic ablation of COX-2, pharmacological inhibition of COX-2 or treatment with the G2-coupled E prostanoid antagonist, AH6809, significantly improved the disease outcome in S. pyogenes infected mice. Therefore, the results of this study open up new perspectives on potential molecular pathways that are prone to pharmacological manipulation during severe streptococcal infections.