Innate Immune Clearance of Host-Adapted Pulmonary Pathogens

摘要 由宿主适应的、多重耐药的细菌病原体引起的肺炎是主要的临床症状。 问题，与原发感染和住院并发症有关。世界上大部分的 与这些病原体相关的病理是由于引起的宿主反应； 导致呼吸衰竭的炎症或免疫抑制反应 畅通无阻的细菌复制、肺损伤和败血症。像MRSA这样的生物， 铜绿假单胞菌和肺炎克雷伯菌很容易适应人体内的环境 获得影响其新陈代谢、免疫原性以及抗药性的突变 抗菌剂。我们研究的目标是应用一种全面的方法来充分描述 这些宿主通过使用全基因组测序，小鼠，从患者分离的病原体 免疫原性和蛋白质组学的建模。这种类型的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。细菌基因是 和甲氧西林一样，可以在临床分离株中实时识别与免疫致病性有关的 耐药基因通常在葡萄球菌中进行筛选。更好地了解主人的反应 即被引出的将被用于应用免疫调节疗法来补充经常无效的 用于治疗肺炎的抗菌剂。在其他医学分支中，针对 炎症体、IL-1、T细胞信号和肿瘤坏死因子级联已成为护理和新免疫的标准 目标正在积极制定中。全面了解这两个属性 感染生物体和被激发的宿主反应可以用来开发一种精确的策略 治疗细菌性肺炎的药物。

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.