Host and microbial factors promoting synergistic mortality during polymicrobial intra-abdominal infections with Candida albicans and Staphylococcus aureus

 描述（由申请人提供）：涉及真菌和细菌病原体的多微生物感染在住院患者中越来越常见。然而，缺乏研究集中在研究多微生物感染。真菌病原体白色念珠菌是侵袭性真菌感染的最常见原因，也是美国医院内血流感染的第三大常见原因。侵袭性真菌感染C.与细菌感染相比，白色念珠菌具有高得惊人的死亡率。血流真菌感染，其中大多数是单一微生物，导致40%的死亡率。相比之下，腹腔内真菌感染（IAI），这往往是涉及真菌和细菌物种的多微生物，导致50-75%的死亡率，这远远超过细菌单一或多微生物IAI死亡率（20%）。真菌参与也导致复发率增加和更严重的疾病评分。与这种死亡率加剧相关的机制目前尚不清楚。本申请的目的是表征在多微生物真菌-细菌腹腔内感染（IAI）期间促成协同致死的宿主和微生物机制。我们的中心假设是，多微生物间细菌腹腔内感染通过诱导局部和全身的病理性炎症反应（脓毒症）促进对死亡率的协同效应。从机制上讲，这种反应是由微生物-微生物相互作用和先天免疫受体的跨界刺激诱导的。该项目的第一个具体目的是检验以下假设：在多微生物真菌-细菌IAI期间观察到的病理性炎症和致死性需要特定的花生酸信号传导途径（考克斯-1; PGE 2; EP 3）。第二个具体目的是检验以下假设：来自真菌和细菌病原体的PRR信号传导是在多微生物IAI期间观察到的增强的类花生酸产生、炎症和致死性所必需的。第三个具体的目的是检验假设，C。白色念珠菌促进细菌毒素产生增加了真菌-细菌多微生物IAI期间的炎症和死亡率。

 DESCRIPTION (provided by applicant): 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.