Dectin-IL-17 axis, candidemia, and aging

描述(由申请人提供)：老年人更容易受到严重感染，年龄是念珠菌血流感染死亡率的唯一最强预测因素。Th17T细胞是最近被描述的一个重要的效应性T细胞亚群，可产生IL-17，并与抗真菌和抗分枝杆菌免疫以及几种自身免疫性疾病有关。通过抗原提呈细胞上的Dectin途径发出的信号促进特定T细胞分化为Th17功能表型。我们的初步数据以及动物数据表明，人类衰老过程中Th17T细胞调节失调，这导致我们提出这样的假设，即人类衰老与Dectin-IL-17轴的变化有关，导致老年人的免疫反应不佳和念珠菌血症的不良后果。这一假说将通过研究人类Dectin-Th17轴的年龄相关变化来验证，并确定Dectin的表达或功能是否减少，并导致老年人Th17反应的失调。此外，我们还将广泛介绍老年人Th17T细胞表型的诱导。我们预计，这些研究将有助于更好地了解老年人免疫反应的调节，并可能有助于识别念珠菌血症后不良结果风险增加的老年人。 与公共健康相关：在这个项目中，我们将研究我们的免疫系统如何随着年龄的增长而变化。我们将专注于免疫系统的一组特定细胞：Th17T细胞。众所周知，这些细胞在对真菌感染的免疫反应中发挥作用。因此，我们还将研究不同年龄段患有严重真菌感染的患者，看看年龄是否影响这些细胞在感染期间的功能。

DESCRIPTION (provided by applicant): Older adults are more susceptible to severe infections and age is the single strongest predictor of mortality in Candida blood stream infections. Th17 T cells are a recently described important subset of effector T cells that produce IL-17 and have been implicated in antifungal and anti-mycobacterial immunity, as well as several auto-immune disorders. Signaling through the Dectin pathway on antigen-presenting cells promotes differentiation of specific T cells to the Th17 functional phenotype. Our preliminary data, as well as animal data suggest a dysregulation of Th17 T cells in human aging leading us to propose the hypothesis that human aging is associated with changes in the Dectin-IL-17 axis resulting in suboptimal immune responses and adverse outcomes in candidemia in older adults. This hypothesis will be tested by studying human age-related changes in the dectin-Th17 axis and determining whether Dectin expression or function is decreased and contributes to dysregulation of Th17 responses in older adults. In addition, we will extensively describe the induction of phenotype of Th17 T cells derived from older adults. We anticipate that these studies will lead to an improved understanding of regulation of immune responses in older adults, and may help to identify older adults at increased risk for adverse outcomes after candidemia. PUBLIC HEALTH RELEVANCE: In this project, we will study how our immune system changes as we get older. We will focus on a specific group of cells of the immune system; Th17 T cells. These cells are known to play a role in the immune response to fungal infections. Therefore, we will also study patients in various age groups who have a serious fungal infection to see if age influences how these cells function during infection.