Priming innate immune responses to infection by cyclooxygenase inhibition kills antibiotic-susceptible and -resistant bacteria.
Inhibition of cyclooxygenase (COX)-derived prostaglandins (PGs) by nonsteroidal anti-inflammatory drugs (NSAIDs) mediates leukocyte killing of bacteria. However, the relative contribution of COX1 versus COX2 to this process, as well as the mechanisms controlling it in mouse and humans, are unknown. Indeed, the potential of NSAIDs to facilitate leukocyte killing of drug-resistant bacteria warrants investigation. Therefore, we carried out a series of experiments in mice and humans, finding that COX1 is the predominant isoform active in PG synthesis during infection and that its prophylactic or therapeutic inhibition primes leukocytes to kill bacteria by increasing phagocytic uptake and reactive oxygen intermediate-mediated killing in a cyclic adenosine monophosphate (cAMP)-dependent manner. Moreover, NSAIDs enhance bacterial killing in humans, exerting an additive effect when used in combination with antibiotics. Finally, NSAIDs, through the inhibition of COX prime the innate immune system to mediate bacterial clearance of penicillin-resistant Streptococcus pneumoniae serotype 19A, a well-recognized vaccine escape serotype of particular concern given its increasing prevalence and multi-antibiotic resistance. Therefore, these data underline the importance of lipid mediators in host responses to infection and the potential of inhibitors of PG signaling pathways as adjunctive therapies, particularly in the con-text of antibiotic resistance.
Stables
Melanie J
MJ
Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London, United Kingdom.
Newson
Justine
J
Ayoub
Samir S
SS
Brown
Jeremy
J
Hyams
Catherine J
CJ
Gilroy
Derek W
DW
D000328:Adult; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D000242:Cyclic AMP / Q000276:immunology / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000276:immunology*; D051546:Cyclooxygenase 2 / Q000276:immunology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000276:immunology; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000187:drug effects; D011008:Pneumococcal Infections / Q000188:drug therapy*; D011453:Prostaglandins / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D055815:Young Adult
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D011453:Prostaglandins; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2