Dectin-IL-17 axis, candidemia, and aging

Dectin-IL-17 轴、念珠菌血症和衰老

• 批准号: 8184779
• 负责人: DAVID VAN DUIN
• 金额: $ 7.85万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8184779
• 关键词: Age; Aging; Antifungal Agents; Antigen-Presenting Cells; Antigens; Biological Assay; Blood; C-Type Lectins; Candida; Candida albicans; Cell physiology; Cells; Chemotaxis; Clinic; Clinical; Clinical Research; Clinical Sciences; Data; Dendritic Cells; Deterioration; Disease; Elderly; Enrollment; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Future; Helper-Inducer T-Lymphocyte; Hospitals; Human; Immune System Diseases; Immune response; Immune system; Immunity; Infection; Interleukin-17; Intervention; Lead; Measures; Membrane Proteins; Methods; Mitogens; Modeling; Mus; Mycobacterium Infections; Mycoses; Outcome; Pathway interactions; Patients; Pattern recognition receptor; Phenotype; Physiological; Play; Proteins; RNA; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; SYK gene; Sepsis; Serum; Signal Transduction; Stimulus; Stream; Surface; T cell differentiation; T memory cell; T-Cell Receptor; T-Lymphocyte; Testing; Translational Research; Vaccination; Western Blotting; adverse outcome; age effect; age group; age related; aged; animal data; base; candidemia; clinically relevant; dectin 1; immunosenescence; improved; monocyte; mortality; mouse dectin-2; mycobacterial; pathogen; peripheral blood; protein expression; response; tertiary care; therapeutic target

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.

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最强预测因素。 Th17 T 细胞是最近描述的效应 T 细胞的重要子集，可产生 I​​L-17，并与抗真菌和抗分枝杆菌免疫以及多种自身免疫性疾病有关。通过抗原呈递细胞上的 Dectin 通路发出的信号可促进特定 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 Th17 T 细胞的失调导致我们提出这样的假设：人类衰老与 Dectin-IL-17 轴的变化有关，导致老年人免疫反应不佳和念珠菌血症的不良后果。该假设将通过研究人类 dectin-Th17 轴中与年龄相关的变化并确定 Dectin 表达或功能是否下降并导致老年人 Th17 反应失调来检验。此外，我们将广泛描述源自老年人的 Th17 T 细胞表型的诱导。我们预计这些研究将加深对老年人免疫反应调节的理解，并可能有助于识别念珠菌血症后不良后果风险增加的老年人。 公共卫生相关性：在这个项目中，我们将研究随着年龄的增长，我们的免疫系统如何变化。我们将重点关注免疫系统的一组特定细胞； Th17 T 细胞。已知这些细胞在针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，看看年龄是否会影响这些细胞在感染期间的功能。