Enhancing Neutrophil Responses to Counter MDR Gram Negative Bacterial Pneumonia

增强中性粒细胞反应以对抗 MDR 革兰氏阴性细菌性肺炎

基本信息

批准号：
9089914
负责人：
Janet Sojung Lee
金额：
$ 20.76万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9089914
关键词：
Amino Acids Antimicrobial Resistance Bacterial Pneumonia Biological Calcium Binding Cathepsin G Cells Clinical Consensus Sequence Containment Critical Illness Cytoplasmic Granules Data Development Economic Burden Elastases Employee Strikes Extracellular Matrix Family Glycoproteins Goals Health Healthcare Immune response Immunity Immunosuppression In Vitro Infection Inflammation Inflammatory Response Injury Klebsiella pneumonia bacterium Length of Stay Leukocyte Elastase Leukocytes Libraries Lung Microfluidics Morbidity - disease rate Mus Patients Phase Pneumonia Protein Family Pseudomonas aeruginosa Recombinants Regimen Reporting Resolution Serine Serine Protease Serine Proteinase Inhibitors Stretching Testing Therapeutic Thrombospondin 1 antimicrobial attributable mortality base efficacy testing extensive drug resistance fighting improved in vivo inhibitor/antagonist killings microbial mortality mouse model neutrophil novel pathogen response small molecule small molecule inhibitor ventilator-associated pneumonia

项目摘要

DESCRIPTION (provided by applicant): The main goal of this application is to test a potential host-directed therapeutic to enhance neutrophil microbial killing of extensively drug resistant (XDR) gram negative pathogens Klebsiella pneumoniae and Pseudomonas aeruginosa that are prevalent in ventilator-associated pneumonia (VAP). The emergence of XDR gram negative pathogens and the limited number of antimicrobial options present a rising challenge for the management of these patients. Enhancing the host immune response to fight infection may afford a novel, adjunct approach to conventional antimicrobials, particularly in critically ill hoss with waning immunity or immunosuppression that are often vulnerable to these pathogens. We have identified a novel mechanism by which thrombospondin-1 (TSP-1), a multifunctional extracellular matrix glycoprotein involved in cell-cell and cell-matrix interactions and released b a variety of cells during inflammation, restrains neutrophil microbial killing through inhibition o neutrophil serine protease (NSP) activity. Our preliminary data indicates that TSP-1 may provide a previously unrecognized, endogenous inhibitory mechanism to counter NSPs and curtail components of the microbial killing arsenal. Previous reports identified regions within the type II repeats domain of TSP-1 that show striking similarity to the consensus sequence found among the Kazal family of serine protease inhibitors. We have recently identified candidate small molecule inhibitors that may target a major cavity created within the type III repeats region of TSP-1. The major hypothesis of this application is that small molecule compounds that potentially disrupt TSP-1/neutrophil serine protease interaction can enhance microbial killing of XDR Klebsiella pneumoniae and Pseudomonas aeruginosa, which are two major VAP pathogens with few treatment options. The R21 is a proof-of-concept "bench" phase where we will examine whether small molecule compounds increase neutrophil microbial killing of XDR clinical isolates in vitro and in vivo using a mouse model. The R33 is the translational or "bedside" phase where we will examine whether TSP-1 based small molecule compounds will improve in vitro microbial killing of XDR pathogens utilizing neutrophils from suspected VAP patients. This approach may serve as the basis for a novel adjunct therapy to existing anti-microbial regimens that reduce bacterial burden in the lungs.

描述（由申请人提供）：本申请的主要目标是测试一种潜在的针对宿主的治疗方法，以增强中性粒细胞微生物对呼吸机相关肺炎中常见的广泛耐药（XDR）革兰氏阴性病原体肺炎克雷伯菌和铜绿假单胞菌的杀灭作用(VAP)。XDR 革兰氏阴性病原体的出现和有限的抗菌药物选择给这些患者的治疗带来了越来越大的挑战。增强宿主免疫反应以对抗感染可能会为传统抗菌药物提供一种新的辅助方法，特别是对于免疫力下降或免疫抑制的危重患者，这些患者往往容易受到这些病原体的影响。 -1) 是一种多功能细胞外基质糖蛋白，参与细胞-细胞和细胞-基质相互作用，并在炎症过程中释放多种细胞，通过抑制中性粒细胞微生物杀伤我们的初步数据表明，TSP-1 可能提供一种以前未被识别的内源性抑制机制来对抗 NSP 并减少微生物杀伤武库的成分。图 1 显示了与 Kazal 丝氨酸蛋白酶抑制剂家族中发现的共有序列惊人的相似性。我们最近发现了可能针对内部产生的主要空腔的候选小分子抑制剂。本申请的主要假设是，潜在破坏 TSP-1/中性粒细胞丝氨酸蛋白酶相互作用的小分子化合物可以增强对 XDR 肺炎克雷伯菌和铜绿假单胞菌（两种主要 VAP 病原体）的微生物杀灭作用。 R21 是一个概念验证“实验”阶段，我们将检查小分子化合物是否能增加中性粒细胞微生物的杀灭作用。使用小鼠模型进行体外和体内 XDR 临床分离。 R33 是翻译或“床旁”阶段，我们将检查基于 TSP-1 的小分子化合物是否会利用来自可疑 VAP 的中性粒细胞改善 XDR 病原体的体外微生物杀灭。这种方法可以作为现有抗微生物疗法的新型辅助疗法的基础，以减少肺部的细菌负荷。