Polymicrobial infections involving fungal and bacterial pathogens are increasingly common among hospitalized patients. However, there is a paucity of research focused on studying polymicrobial infections. The fungal pathogen Candida albicans is the most common cause of invasive fungal infection and the third most common cause of nosocomial bloodstream infections in the US. Invasive fungal infections with C. albicans have devastatingly high mortality rates compared with bacterial infections. Bloodstream fungal infections, which are mostly monomicrobial, result in a 40% mortality rate. In contrast, intra-abdominal fungal infections (IAI), which are often polymicrobial involving both fungal and bacterial species, result in a 50-75% mortality rate, which far exceeds bacterial mono- or polymicrobial IAI mortality rates (20%). Fungal involvement also leads to increased rates of relapse and more severe disease scores. The mechanisms associated with this exacerbated mortality are currently unknown. The objective of this application is to characterize the host and microbial mechanism/s contributing to synergistic lethality during polymicrobial fungal-bacterial intra-abdominal infections (IAI). Our central hypothesis is that polymicrobial Candida-bacterial intra-abdominal infections promote synergistic effects on mortality by inducing a pathological inflammatory response locally and systemically (sepsis). Mechanistically, the response is induced by both microbe-microbe interactions and cross-kingdom stimulation of innate immune receptors. The first specific aim of this project is to test the hypothesis that specific eicosanoi signaling pathways (COX-1; PGE2; EP3) are required for pathological inflammation and lethality observed during polymicrobial fungal-bacterial IAI. The second specific aim is to test the hypothesis that PRR signaling from both fungal and bacterial pathogens is required for enhanced eicosanoid production, inflammation, and lethality observed during polymicrobial IAI. The third specific aim is to test the hypothesis that C. albicans promotion of bacterial toxin production augments inflammation and mortality during fungal-bacterial polymicrobial IAI.
This application seeks to characterize novel host and microbial mechanisms promoting synergistic mortality observed during lethal polymicrobial IAI with Candida albicans and Staphylococcus aureus using a well-developed murine model of polymicrobial IAI. A goal of this work is to challenge current clinical paradigms related to this devastating disease and identify potential points during the host response that can be targeted pharmacologically following infection that would provide new information that could be used clinically to reduce mortality in IAI patients. These studies also have the potential for broad impact, as Candida albicans also exerts synergistic mortality during intraperitoneal infections with other enteric pathogens.
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