Pulmonary gamma-delta T cells in lung infection

肺部感染中的肺 γ-δ T 细胞

• 批准号: 10187880
• 负责人: Shelton Wiley Wright
• 金额: $ 16.08万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10187880
• 关键词: Address; Aerosols; Animal Model; Applications Grants; Bacteria; Bacterial Vaccines; Blood donor; Burkholderia; Burkholderia pseudomallei; Cells; Cessation of life; Characteristics; Childhood; Complement; Containment; Critical Illness; Data; Development; Development Plans; Disease; Disease model; Fatality rate; Fc Receptor; Foundations; Gene Expression; Genes; Goals; Health; Hospitalization; Host Defense; Host resistance; Human; Immune response; Immune system; Immunology; Immunotherapy; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Intensive Care; Interferon Type II; Interleukin-17; K-Series Research Career Programs; Leukocytes; Lower Respiratory Tract Infection; Lung; Lung Inflammation; Lung infections; Lymphocyte; Melioidosis; Mentors; Mentorship; Methods; Modeling; Mucous Membrane; Mus; Neutrophil Infiltration; Patient Recruitments; Patients; Peripheral; Phenotype; Physicians; Play; Pneumonia; Positioning Attribute; Process; Prospective Studies; Receptor Cell; Research; Research Personnel; Research Project Grants; Role; Scientist; Soil; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte Subsets; Testing; Therapeutic; Tissues; Training; Training Programs; Training and Infrastructure; United States; Universities; Washington; base; bioweapon; career development; cohort; community acquired pneumonia; cytokine; differential expression; human model; immunomodulatory therapies; improved; in vivo; innovation; insight; knockout animal; mouse model; multidisciplinary; neutrophil; novel; pathogen; peripheral blood; pneumonia model; programs; single-cell RNA sequencing; transcriptomics; translational approach; translational physician; translational research program; translational scientist; γδ T cells

PROJECT SUMMARY Lower respiratory tract infections, including pneumonia, are the most common cause of infection-related death worldwide. γδ T cells are highly conserved leukocytes possessing innate-like immune response characteristics. Enriched in the mucosa, γδ T cells may play an outsized role in regulating pulmonary inflammatory responses and have been proposed as a basis for novel immunotherapies. However, data concerning the inflammatory role of pulmonary γδ T cells during pneumonia in humans are limited. Dr. Shelton Wright is a pediatric intensive care physician-scientist whose goal is to obtain the necessary training to become an independent translational investigator of pulmonary host defense. He has established a translational research program that has identified a critical role of γδ T cells in pulmonary melioidosis, a highly lethal cause of pneumonia. Based on these findings, he has developed a central hypothesis that host resistance to pulmonary melioidosis is dependent on an IL-17+ γδ T cell inflammatory response. Dr. Wright's research goal is to determine the mechanisms underlying the host γδ T cell inflammatory response during severe lung infection. Using pulmonary melioidosis as a model for severe lung infection, Dr. Wright will test his hypothesis through the following 3 Aims: 1) Determine the role of γδ T cells in lung inflammation during pulmonary melioidosis in vivo; 2) Identify differential human γδ T cell inflammatory responses to B. pseudomallei infection in the ex-vivo lung compared to peripheral blood; and 3) Characterize γδ T cell activation in patients with early pulmonary melioidosis. The Career Development Plan for this grant proposal will provide Dr. Wright with critical training in pulmonary immunology, transcriptomics and high containment pathogen research. Dr. Wright has leveraged the outstanding training infrastructure at the University of Washington and its affiliates to bring together a wide array of experts in these fields to provide targeted mentorship for this proposal. Dr. Wright's multidisciplinary team of mentors will greatly complement his proposed research project along with a carefully selected didactic program. The data generated by his proposal and the skillsets developed from his training program will significantly facilitate Dr. Wright's goal of developing into an independent translational physician-scientist investigating the mechanisms of pulmonary host defense during severe lung infection.

项目总结 包括肺炎在内的下呼吸道感染是与感染有关的死亡的最常见原因 全世界。γδT细胞是高度保守的白细胞，具有先天免疫反应特性。 富含在粘膜中的γδT细胞可能在调节肺炎性反应中发挥过大作用 并已被提议作为新的免疫疗法的基础。然而，关于炎症性疾病的数据 肺γδT细胞在人类肺炎中的作用有限。谢尔顿·赖特医生是儿科医生 重症监护内科医生-科学家，他的目标是获得必要的培训以成为 肺宿主防御的独立翻译调查员。他已经建立了一个翻译公司 一项研究计划确定了γδT细胞在肺类鼻疽病中的关键作用，这是一种高度致命的原因 肺炎的症状。基于这些发现，他提出了一个中心假设，即宿主对 肺类鼻炎依赖于IL-17+γδT细胞的炎症反应。 赖特博士的研究目标是确定宿主γδT细胞炎症反应的潜在机制 在严重的肺部感染期间。利用肺类鼻疽病作为严重肺部感染的模型，Wright博士将 通过以下3个目标验证他的假设：1)确定γδT细胞在肺部炎症中的作用 2)鉴定人γδT细胞对B细胞的不同炎症反应。 体外肺与外周血中假鼻孔感染的比较；3)γδT细胞的特征 早期肺类鼻炎患者的激活状态。 这项拨款提案的职业发展计划将为赖特博士提供关键的肺科培训 免疫学、转录学和高遏制病原体研究。赖特博士利用 华盛顿大学及其附属机构卓越的培训基础设施将广泛的 这些领域的一系列专家为这项建议提供有针对性的指导。莱特博士的多学科研究 导师团队将极大地补充他提出的研究项目，以及精心挑选的教学方法 程序。他的提案产生的数据和他的培训计划开发的技能集将 极大地促进了赖特博士发展成为一名独立的翻译内科科学家的目标 探讨重症肺部感染时的肺宿主防御机制。