Bacterial infections are a major cause of morbidity and mortality worldwide. Innovative approaches to their prevention and management are needed. New treatments have focused on discovering antibiotics but this is problematic given the rise of antimicrobial drug resistance in common bacterial pathogens. Recent attention has been placed on identifying immunomodulatory agents that enhance innate and/or adaptive immune defenses of the infected host.2 The present work by Stables et al advances this immunopharmacology paradigm as it pertains to bacterial infections.1 Their work suggests that one solution may lie within the biology of aspirin. Stables and collaborators used pharmacologic and genetic techniques to determine whether prostaglandin (PG) synthesis and signaling alters host immune responses to infections caused by either group B Streptococcus (GBS) or Streptococcus pneumoniae. Through elegant human and murine studies, Stables et al found that the inhibition of the PG-synthesizing cyclooxygenase-1 (COX-1) and COX-2 enzymes significantly improved innate immune defenses against common streptococcal pathogens. In so doing, they have brought several previously (and disparately) characterized immunomodulatory actions of PGs together. Their studies characterized several PG receptors and the intracellular signaling molecule (cAMP) involved in suppressing host defenses against infection. Strengths of the experimental design by Stables et al include the combined use of rodent and human infection models to explore host-microbial interactions.1 Notably, their findings were reproducible when studying either antibiotic-susceptible or -resistant S pneumoniae. This is interesting and important because the class of COX inhibitors used in these studies, the nonsteroidal antiinflammatory drugs (NSAIDs), is in common clinical use, raising the question of whether such medications might one day be used as adjuvant therapy in the treatment of antibiotic-resistant bacterial infections. The PGs, oxygenated metabolites of the cell-membrane phospholipid component arachidonic acid, are generated rapidly in the face of physiologic or pathophysiologic perturbation. Unlike proteins, PGs are produced almost immediately upon cell stimulation, without relying on gene transcription and translation. They are important in many nonimmune physiologic processes, explaining the utility of aspirin in preventing arterial thrombosis (by reducing platelet thromboxane A2 production) and the adverse effects of NSAIDs such as gastric ulceration and renal toxicity. During infection, PGs have complex actions, both driving and relaxing host responses. PGE2, the archetype immunoregulatory PG, promotes inflammation by inducing endothelial cell–mediated vasodilatation (producing warmth, erythema, and edema), and supporting Th17 adaptive immune responses.3 However, as supported by Stables et al, PGE2 has potent antiinflammatory and immunosuppressive properties including the direct inhibition of: neutrophil chemotaxis and activation; leukocyte reactive oxygen intermediate production; phagocytosis; bacterial killing; and the generation of myriad proinflammatory cytokines, chemokines, and lipids.4 Conversely, PGE2 enhances the production of the antiinflammatory cytokine interleukin-10 and stimulates the expression of the suppressor of cytokine signaling-3 protein.4 In general, the inhibitory effects of PGE2, and the closely related PGI2, result from cAMPdependent signaling processes triggered by EP2 and EP4 receptor binding, and IP receptor activation for PGI2 (see figure). These immunosuppressive actions of PGs likely evolved to prevent inflammatory tissue damage and promote the resolution of inflammation.5 Aspirin and other NSAIDs have been used in patients with febrile infections for thousands of years, if one considers salicylatecontaining botanicals. In 1962, Northover and Prostaglandin signaling suppresses innate defense functions of monocytes and macrophages. In this depiction, the prostaglandins PGE2 and prostacyclin (PGI2) trigger the intracellular production of the second messenger cAMP through the activation of Gs-coupled receptors on monocytes or macrophages. PGE2 evokes cAMP through EP2 and EP4 receptors while PGI2 does so through the IP receptor. cAMP-signaling cascades impair 3 primary functions of these innate immune cells: phagocytosis, intracellular killing, and the induction of inflammatory mediators (cytokines, chemokines, and lipids) by cells infected with bacterial pathogens. NFB, the transcription factor nuclear factor B; and PRR, pathogen recognition receptor (eg, Toll-like receptors). Red bars indicate inhibitory signaling pathways.