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

• 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
• 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

 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性肺炎（VAP）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。 XDR 革兰氏阴性病原体的出现和有限数量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颖的辅助方法，特别是对于免疫力下降或免疫抑制且往往容易受到这些病原体侵害的危重患者。我们发现了一种新机制，血小板反应蛋白-1 (TSP-1) 是一种参与细胞-细胞和细胞-基质相互作用的多功能细胞外基质糖蛋白，在炎症过程中由多种细胞释放，通过抑制中性粒细胞丝氨酸蛋白酶 (NSP) 活性来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认识的内源性抑制机制来对抗 NSP 并减少微生物杀伤库的成分。先前的报告鉴定了 TSP-1 的 II 型重复结构域内的区域，这些区域与 Kazal 丝氨酸蛋白酶抑制剂家族中发现的共有序列具有惊人的相似性。我们最近发现了候选小分子抑制剂，它们可能靶向 TSP-1 III 型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对 XDR 肺炎克雷伯菌和铜绿假单胞菌的微生​​物杀灭，这两种主要的 VAP 病原体几乎没有治疗选择。 R21 是一个概念验证“试验台”阶段，我们将使用小鼠模型在体外和体内检查小分子化合物是否会增加中性粒细胞微生物对 XDR 临床分离株的杀伤力。 R33 是翻译或“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来自疑似 VAP 患者的中性粒细胞改善对 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担。