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

 描述(申请人提供)：涉及真菌和细菌病原体的多菌感染在住院患者中越来越常见。然而，专注于研究多菌感染的研究很少。真菌病原体白色念珠菌是侵袭性真菌感染的最常见原因，也是美国医院血流感染的第三大常见原因。与细菌感染相比，白色念珠菌侵袭性真菌感染的死亡率高得惊人。血流真菌感染，主要是单一微生物感染，导致40%的死亡率。相比之下，腹内真菌感染(IAI)通常是涉及真菌和细菌物种的多菌感染，其死亡率为50%-75%，远远超过细菌单一或多菌IAI死亡率(20%)。真菌感染还会增加复发率和更严重的疾病评分。与这种加剧死亡率有关的机制目前尚不清楚。这项应用的目的是表征宿主和微生物在多菌真菌-细菌腹内感染中协同致死作用的机制/S。我们的中心假设是，多菌假丝酵母菌-细菌腹内感染通过诱导局部和全身的病理炎症反应(脓毒症)，促进了死亡率的协同效应。从机制上讲，这种反应既是由微生物-微生物相互作用引起的，也是由天然免疫受体的跨王国刺激引起的。这个项目的第一个具体目标是检验这样一个假设，即在多菌真菌-细菌IAI期间观察到的病理炎症和致死性需要特定的二十碳信号通路(COX-1；PGE2；EP3)。第二个特定的目的是检验这一假设，即在多菌IAI期间观察到来自真菌和细菌病原体的PRR信号对于增加二十烷类化合物的产生、炎症和致死性是必需的。第三个具体目标是测试假设，在真菌-细菌多菌IAI期间，白色念珠菌促进细菌毒素产生会增加炎症和死亡率。

 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.