Cellular and Molecular Mechanisms of Fungal Sepsis in the Critically Ill Patient

摘要 机会性真菌引起的侵袭性感染在外科ICU中越来越常见。 ICU患者真菌性败血症的死亡率为30 - 40%。人们普遍认为， 在脓毒症的发病率中起关键作用，年龄是已知的脓毒症的独立预测因子。 败血症死亡率。真菌感染已成为老年ICU患者日益严重的问题。 这部分是由于脓毒症导致免疫抑制的事实。但也 众所周知，健康的老年人表现出免疫功能的衰老。此外， 患者经常有多种合并症，并经历更多的侵入性手术， 患败血症的风险更高潜在的细胞和分子机制，导致 老年和/或脓毒症患者对真菌感染的易感性增加并不完全 明白本申请中概述的研究重点是解决我们在 知识我们获得的初步数据表明，健康的老年人 个人（> 60岁）显示出降低的抗真菌Th17介导的应答， 年轻的健康对照。我们也有初步的数据表明临床败血症 减少白细胞Dectin-1的表达，Dectin-1是白细胞的主要模式识别受体， 诱导抗真菌先天免疫。根据这些数据和已发表的文献， 假设"老年重症患者对真菌性脓毒症易感性是由 抗真菌先天免疫中的特定细胞和分子缺陷"。为了验证我们的假设， 提出以下三个具体目标。在目标1中，我们将确定与年龄相关的缺陷， 来自60岁以上健康成年人的人白细胞中的Dectin-1/Th17依赖性信号传导我们将 检测Dectin-1/Th17介导的细胞内信号传导对白色念珠菌或念珠菌的应答。 > 60岁成人白细胞中的白色念珠菌细胞壁葡聚糖并将它们与 成人<30岁在目标2中，我们将鉴定在细胞中Dectin-1/Th17依赖性信号传导的缺陷。 脓毒症患者的白细胞为此，我们将严格评估Dectin-1/Th17 脓毒症患者白细胞中响应白色念珠菌或葡聚糖的介导信号传导 并将其与年龄匹配的健康成年人进行比较。在目标3中，我们将研究 临床脓毒症对人白细胞Dectin-1表达的影响。我们将Dectin-1表达与 感染类型、急性生理学评分和损伤指数、住院时间， ICU天数和生存结局。这些实验将提供新的知识 使老年重症患者易受危及生命的真菌感染的机制 感染.此外，我们将获得新的临床数据，这些数据可能会发现新的预测因子， 易受真菌感染。最后，我们将研究增加对 危重病人的机会性真菌感染

Abstract Invasive infections caused by opportunistic fungi are increasingly common in the surgical ICU. The mortality rate for fungal sepsis in the ICU patient is 30-40%. It is well accepted that aging plays a critical role in the incidence of sepsis and age is a known independent predictor of mortality in sepsis. Fungal infections have become an increasing problem in older ICU patients. This is due, in part, to the fact that sepsis results in immune suppression. However, it is also known that healthy aged adults show senescence of immune function. In addition, aging patients frequently have multiple co-morbidities and undergo more invasive procedures leading to a higher risk of sepsis. The underlying cellular and molecular mechanisms that result in increased susceptibility to fungal infection in the aged and/or septic patient are not fully understood. The research outlined in this application is focused on addressing that deficit in our knowledge. We have acquired preliminary data which demonstrate that healthy aged individuals (>60 y.o.) show decreased anti-fungal Th17 mediated responses when compared to young healthy controls. We also have preliminary data which indicate that clinical sepsis decreases leukocyte expression of Dectin-1, the primary pattern recognition receptor for induction of anti-fungal innate immunity. Based on these data and the published literature we hypothesize that “susceptibility to fungal sepsis in the aged critically ill patient is mediated by specific cellular and molecular defects in anti-fungal innate immunity”. To test our hypothesis we propose the three following specific aims. In aim 1 we will identify the age related defects in Dectin-1/Th17 dependent signaling in human leukocytes from healthy adults >60 y.o. We will examine Dectin-1/Th17 mediated intracellular signaling in response to Candida albicans or C. albicans cell wall glucan in leukocytes from adults >60 y.o. and compare them to those from adults <30 y.o. In aim 2 we will identify defects in Dectin-1/Th17 dependent signaling in leukocytes from patients with sepsis. In this aim we will critically evaluate Dectin-1/Th17 mediated signaling in response to Candida albicans or glucan in leukocytes from septic patients and compare them to age matched healthy adults. In aim 3 we will investigate the impact of clinical sepsis on human leukocyte Dectin-1 expression. We will correlate Dectin-1 expression with the type of infection, acute physiology scores and injury indices, length of hospital stay, days in ICU and survival outcome. These experiments will provide new knowledge of the mechanisms that render the aged critically ill patient susceptible to life threatening fungal infections. In addition, we will acquire new clinical data that may identify novel predictors of susceptibility to fungal infection. Finally, we will investigate strategies to increase resistance to opportunistic fungal infections in the critically ill patient.