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：
8951695
负责人：
Janet Sojung Lee
金额：
$ 22.11万
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8951695
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 Extreme drug resistant tuberculosis Family Glycoproteins Goals 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 fighting improved in vivo inhibitor/antagonist killings microbial mortality mouse model neutrophil novel pathogen public health relevance response small molecule 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（通过应用程序提供）：本应用的主要目标是测试潜在的宿主指导疗法，以增强杀害广泛耐药性（XDR）革兰氏耐药性病原体的嗜中性粒细胞微生物杀死Klebsiella肺炎klebsiella pneumoniae和pseudomonas aeruginosa，这些病原体普遍存在vintilator-aeruginosa。 XDR革兰氏阴性病原体的出现和抗菌选择数量有限，对这些患者的治疗提出了增加的挑战。增强宿主免疫反应对抗感染可能会提供一种新颖的，辅助的方法，尤其是在批判性地批判性地降低了免疫学或免疫抑制，通常容易受到这些病原体的影响。我们已经确定了一种新的机制，该机制通过该机制，通过这种机制，通过抑制中性粒细胞中性粒细胞中性粒细胞中性粒细胞蛋白蛋白蛋白蛋白酶（NSP），炎症过程中涉及细胞细胞和细胞相互作用的多功能细胞外基质糖蛋白，并限制中性粒细胞微生物在炎症过程中释放多种细胞。我们的初步数据表明，TSP-1可能会提供先前未知的内源性抑制作用机制来反击微生物杀伤库的NSP和减少成分。先前的报道确定了TSP-1型II型重复域内的区域，这些区域与丝氨酸蛋白酶抑制剂的Kazal家族中发现的共识序列相似。我们最近确定了候选小分子抑制剂，该抑制剂可能针对TSP-1型III重复区域内产生的主要空腔。该应用的主要假设是，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XDR klebsiella肺炎和铜绿假单胞菌的微生物杀死，这是两种主要的VAP病原体，具有少数治疗选择。 R21是概念验证“基准”阶段，我们将检查小分子化合物是否会在体外和使用小鼠模型的体外和体内增加XDR临床分离株的中性粒细胞微生物杀死。 R33是转化或“床边”阶段，我们将检查基于TSP-1的小分子化合物是否会利用可疑VAP患者的中性粒细胞改善XDR病原体的体外微生物杀死。这种方法可以作为对现有抗菌方案的新型辅助疗法的基础，从而减少细菌燃烧的肺部燃烧。