Innate Immune Clearance of Host-Adapted Pulmonary Pathogens

适应宿主的肺部病原体的先天免疫清除

• 批准号: 10317092
• 负责人: Alice S Prince
• 金额: $ 86.24万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-11 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317092
• 关键词: Affect; Antimicrobial Resistance; Bacterial Genes; Bacterial Pneumonia; Caring; Clinical; Complement; Data; Development; Genus staphylococcus; Goals; Hospitalization; Human; Immune Targeting; Immune response; Infection; Inflammasome; Inflammation; Interleukin-1; Klebsiella pneumoniae; Link; Medicine; Metabolism; Methicillin Resistance; Multi-Drug Resistance; Mutation; Organism; Pathogenicity; Pathology; Patients; Pattern; Pneumonia; Primary Infection; Property; Proteomics; Pseudomonas aeruginosa; Respiratory Failure; Sepsis; Signal Transduction; T-Lymphocyte; TNF gene; Time; antimicrobial drug; immune clearance; immunogenicity; immunomodulatory therapies; improved outcome; lung injury; lung pathogen; methicillin resistant Staphylococcus aureus; mouse model; pathogen; pathogenic bacteria; pneumonia treatment; precision medicine; resistance gene; response; routine screening

Abstract Pneumonia caused by host-adapted, multiple drug resistant bacterial pathogens is a major clinical problem, associated with both primary infections and complications of hospitalization. Much of the pathology associated with these pathogens is due to the host response that is elicited ; either excessive inflammation that causes respiratory failure or an immunosuppressive response that permits unimpeded bacterial replication, pulmonary damage and sepsis. Organisms such as MRSA, Pseudomonas aeruginosa and Klebsiella pneumoniae readily adapt to the milieu within the human airways, acquiring mutations that affect their metabolism, immunogenicity as well as their resistance to antimicrobial agents. The goal of our studies is to apply a comprehensive approach to fully characterize such host adapted pathogens, isolated from patients, by using whole gen ome sequencing, murine modeling of immunogenicity, and proteomics. This type of analysis can provide the data necessary to identify bacterial components associated with specific patterns of infection. Bacterial genes that are linked to immuno-pathogenicity can be identified in clinical isolates in real time, just as methicillin resistance genes are routinely screened in staphylococci. A better understanding of the host response that is elicited will be used to apply immunomodulatory therapy to complement the often ineffective antimicrobial agents used to treat pneumonia. In other branches of medicine, targeting the inflammasome, IL-1, T cell signaling and TNF cascades have become standards of care and new immune targets are under active development. A comprehensive understanding of both the properties of the infecting organism and the host response that is evoked can be used to develop a strategy of precision medicine for the treatment of bacterial pneumonia.

摘要 由宿主适应性、多重耐药细菌病原体引起的肺炎是临床上的主要疾病， 问题，与原发性感染和住院并发症有关。大部分 与这些病原体相关的病理是由于引起的宿主反应;过度的 导致呼吸衰竭或免疫抑制反应的炎症， 无阻碍的细菌复制、肺损伤和败血症。微生物如MRSA， 铜绿假单胞菌和肺炎克雷伯菌容易适应人体内的环境， 气道，获得影响其代谢，免疫原性以及其抵抗力的突变， 抗菌剂。我们研究的目标是应用一种全面的方法， 通过使用全基因组测序，从患者分离的这种宿主适应性病原体， 免疫原性建模和蛋白质组学。这种分析可以提供必要的数据， 确定与特定感染模式相关的细菌成分。细菌基因 与免疫致病性相关的甲氧西林可以在临床分离株中真实的时间内被鉴定出来， 通常在葡萄球菌中筛选抗性基因。更好地了解宿主的反应 将用于应用免疫调节治疗，以补充通常无效的 用于治疗肺炎的抗菌剂。在其他医学分支中， 炎性小体、IL-1、T细胞信号传导和TNF级联已成为护理标准和新的免疫调节剂。 目标正在积极制定中。全面了解这两个属性的 感染生物体和引起的宿主反应可用于开发精确的策略 治疗细菌性肺炎的药物。