Identification of Specific Components of the Eicosanoid Biosynthetic and Signaling Pathway Involved in Pathological Inflammation during Intra-abdominal Infection with Candida albicans and Staphylococcus aureus

Abstract

Polymicrobial intra-abdominal infections (IAIs) are a significant cause of morbidity and mortality, particularly when fungal pathogens are involved. Our experimental murine model of IAI involving intraperitoneal inoculation of <i>Candida albicans</i> and <i>Staphylococcus aureus</i> results in synergistic lethality (∼80%) due to exacerbated inflammation. Monomicrobial infection results in no mortality, despite a microbial burden and dissemination similar to those in a coinfection. In the coinfection model, the immunomodulatory eicosanoid prostaglandin E₂ (PGE₂) was determined to be necessary and sufficient to induce mortality, implicating PGE₂ as the central mediator of the amplified inflammatory response. The aim of this study was to identify key components of the PGE₂ biosynthetic and signaling pathway involved in the inflammatory response and explore whether these can be targeted to prevent or reduce mortality. Using selective pharmacological inhibitors of cyclooxygenases (COX) or PGE₂ receptor antagonists in the <i>C. albicans</i>-<i>S. aureus</i> IAI mouse model, we found that inhibition of COX and/or blocking of PGE₂ receptor 1 (EP1) or PGE₂ receptor 3 (EP3) signaling reduced proinflammatory cytokine production, promoted interleukin-10 production, reduced cellular damage in the peritoneal cavity, and, most importantly, significantly improved survival. The greatest effect on survival was obtained by the simultaneous inhibition of COX-1 activity and EP1 and EP3 receptor signaling. Importantly, early inhibition of PGE₂ pathways dramatically improved the survival of fluconazole-treated mice compared with that achieved with fluconazole treatment alone. These findings indicate that COX-1 and the EP1 and EP3 receptors mediate the downstream pathological effects of PGE₂ during polymicrobial IAI and may serve as effective therapeutic targets.