Genetically engineered macrophages to treat pulmonary infections

基因工程巨噬细胞治疗肺部感染

• 批准号: 9977009
• 负责人: Courtney Crane
• 金额: $ 27.61万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-06 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977009
• 关键词: Acute; Adoptive Transfer; Anti-Bacterial Agents; Antibiotics; Antibodies; Antimicrobial Resistance; Australia; Bacterial Model; Bacterial Pneumonia; Bacterial Proteins; Biological Response Modifiers; Biology; Bone Marrow; Brain Neoplasms; Burkholderia pseudomallei; CD19 gene; Cells; Cellular immunotherapy; Cephalosporins; Cessation of life; Clinical Trials; Community Healthcare; Development; Discipline; Engineering; Etiology; Gene Expression; Generations; Genetic Engineering; Home environment; Homologous Gene; Host Defense; Host resistance; Human; Immunotherapy; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-12; Intravenous; Klebsiella pneumoniae; Length; Length of Stay; Lung; Lung diseases; Lung infections; Melioidosis; Modeling; Morbidity - disease rate; Mus; Nosocomial pneumonia; Organism; Pneumonia; Proteins; Public Health; Reporting; Research Personnel; Resistance; Respiratory Tract Infections; Route; Site; Solid Neoplasm; Southeastern Asia; System; Testing; Therapeutic; antimicrobial peptide; biothreat; cancer immunotherapy; carbapenem resistance; cathelicidin; chimeric antigen receptor T cells; cytokine; extracellular; flexibility; improved; improved outcome; in vivo; innovation; macrophage; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; pathogen; resistant strain; respiratory; therapy resistant

PROJECT SUMMARY Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Increasing antimicrobial resistance among common agents of bacterial pneumonia necessitates the development of new therapeutic strategies. In this project, we focus on two resistant pathogens that are public health threats. Burkholderia pseudomallei (BP) is a common etiology of pneumonia (pneumonic melioidosis) in Southeast Asia and northern Australia. Pneumonic melioidosis is lethal in 22-50% of cases despite treatment. BP is a facultative intracellular pathogen that is inherently resistant to many antibiotics and requires prolonged courses of therapy. Klebsiella pneumoniae (KP) is an extracellular pathogen that is a well known cause of community- and healthcare-associated pneumonia. KP has become increasingly resistant to carbapenems and third generation cephalosporins. Infections caused by resistant strains of KP are difficult to treat, prolong hospital stays, and are associated with high mortality. BP and KP are representative of the urgent need to develop new therapies to treat resistant lung infections. This project brings together three investigators from distinct disciplines to tackle this challenge. Drs. West and Skerrett are established researchers in pulmonary host defense against bacterial lung infections. They have created murine models of bacterial respiratory infection including BP (and surrogate organism, B. thailandensis) infection and KP. These bacterial respiratory infection models have been used to investigate host and bacterial factors and to evaluate therapeutics. Dr. Crane, a cancer immunotherapy researcher, has developed a novel and flexible system to create genetically engineered macrophages (GEMs) to produce a range of secreted proteins over a month in vitro or in vivo. Administered intravenously to mice, GEMs accumulate at high levels in the lungs for at least 4 days. Others have reported that airway delivery of macrophages results in durable localization of these cells within the lungs for months. Thus, intravenous or pulmonary delivery of GEMs may be a novel, versatile therapeutic strategy against lung infections. The central hypothesis of this proposal is that GEMs that produce pro-inflammatory and/or antimicrobial peptides and home to the site of infection can augment host resistance to respiratory infections caused by pathogens such as BP and KP. This hypothesis will be tested as follows: Aim 1. Develop and test GEMs with enhanced bacterial killing functions that produce the cytokine interleukin 12 (IL-12) or antimicrobial peptide CRAMP (the mouse homolog of human cathelicidin). Aim 2. Define localization and the inflammatory responses induced by IL-12- or CRAMP-expressing GEMs adoptively transferred in vivo. Aim 3. Determine whether the adoptive transfer of IL-12- or CRAMP-expressing GEMs augments resistance to acute bacterial pneumonia caused by B. thailandensis or K. pneumoniae. This innovative project tests two novel and potentially synergistic therapies for resistant yet distinct pathogens causing pneumonia. Moreover, the highly adaptable and tunable GEM platform is potentially very relevant to a wide variety of other lung infections and lung diseases.

项目概要 细菌性肺炎是全世界发病和死亡的主要原因。增加抗菌剂 细菌性肺炎常见病原体的耐药性需要开发新的治疗方法 策略。在这个项目中，我们重点关注两种对公共卫生构成威胁的耐药病原体。伯克霍尔德杆菌 假鼻疽 (BP) 是东南亚肺炎（肺炎类鼻疽）的常见病因 澳大利亚北部。尽管接受了治疗，但仍有 22-50% 的肺炎病例是致命的。 BP是兼性的 细胞内病原体，对许多抗生素具有固有耐药性，需要长期治疗。 肺炎克雷伯菌 (KP) 是一种细胞外病原体，是引起社区和社区感染的众所周知的原因。 医疗相关肺炎。 KP 对碳青霉烯类和第三代的耐药性越来越强 头孢菌素类。 KP 耐药菌株引起的感染难以治疗、延长住院时间，并且 与高死亡率相关。 BP 和 KP 代表了开发新疗法的迫切需要 治疗耐药性肺部感染。该项目汇集了来自不同学科的三名研究人员来解决 这个挑战。博士。 West 和 Skerrett 是肺部宿主防御细菌方面的知名研究人员 肺部感染。他们创建了细菌性呼吸道感染的小鼠模型，包括 BP（以及替代品） 有机体（B. thailandensis）感染和 KP。这些细菌呼吸道感染模型已被用于 研究宿主和细菌因素并评估治疗方法。 Dr. Crane，癌症免疫疗法 研究人员开发了一种新颖且灵活的系统来创建基因工程巨噬细胞（GEM） 在体外或体内一个月内产生一系列分泌蛋白。对小鼠进行静脉注射， GEM 在肺部以高水平积聚至少 4 天。其他人报告说，气道输送 巨噬细胞导致这些细胞在肺部持久定位数月。因此，静脉注射或 GEM 的肺部递送可能是一种新颖的、多功能的肺部感染治疗策略。中央 该提案的假设是，产生促炎和/或抗菌肽的 GEM 感染部位的所在地可以增强宿主对由病原体引起的呼吸道感染的抵抗力，例如 如 BP 和 KP。该假设将按如下方式进行检验： 目标 1. 开发和测试具有增强功能的 GEM 产生细胞因子白细胞介素 12 (IL-12) 或抗菌肽 CRAMP（ 人导管素的小鼠同系物）。目标 2. 定义定位和诱导的炎症反应 表达 IL-12 或 CRAMP 的 GEM 在体内过继转移。目标 3. 确定是否收养 表达 IL-12 或 CRAMP 的 GEM 的转移可增强对由以下原因引起的急性细菌性肺炎的抵抗力： 泰国伯克利杆菌或肺炎克雷伯菌。这个创新项目测试了两种新颖且具有潜在协同作用的疗法 针对引起肺炎的耐药但独特的病原体。此外，高度适应性和可调性的 GEM 平台可能与多种其他肺部感染和肺部疾病非常相关。