Therapeutic Potential of Cystatin 9 Treatment to Fight Bacterial Pneumonia

 描述（由申请方提供）：耐药细菌性肺炎可诱导炎症失调，引起急性肺损伤（ALI）/急性呼吸窘迫综合征（ARDS），导致成人和儿童人群的高发病率和死亡率。目前的抗微生物剂和/或抗炎剂通常不能调节炎症级联反应的程度和强度，导致免疫功能失衡，增加继发感染的风险。我们已经鉴定了人蛋白质胱抑素9（CST 9）作为一种新型且有效的免疫治疗方法，通过调节致病性炎症同时促进有益的免疫应答来治疗其他耐药细菌感染。 我们的建议集中在进一步评估人类半胱氨酸蛋白酶抑制剂CST 9及其作为一种新的治疗剂对肺炎相关的肺部炎症的发展。我们的研究结果显示了人重组体（rCST 9）的多方面免疫调节和抗菌功能，从而调节肺泡上皮细胞和巨噬细胞炎症，增强对各种革兰氏阴性病原体的抗菌免疫反应，保护肺完整性并直接干扰细菌病原体复制。我们假设rCST 9将调节炎症以对抗肺损伤并改善由耐药德里金属β-内酰胺酶-1（NDM-1）产生的肺炎克雷伯菌（Kp）引起的肺炎实验模型中的宿主存活率。本提案的目标和创新将是优化rCST 9疗效，作为转化为药物开发（R33阶段）所必需的肺炎对策（R21阶段）。我们并不认为rCST 9是治疗肺部炎症性疾病的“灵丹妙药”。但我们的数据强烈支持rCST 9对免疫应答和病原体毒力的不同影响，使其非常适合作为一种有前途的治疗方法（可以单独使用或伴随其他治疗方法）对肺部病原体进行更深入的分析。

 DESCRIPTION (provided by applicant): Drug-resistant bacterial pneumonia can induce dysregulated inflammation causing acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) leading to high morbidity and mortality in adult and pediatric populations. Current antimicrobial and/or anti-inflammatory agents typically fail to modulate the extent and intensity o the inflammatory cascade, resulting in an imbalance of immune functions, increasing the risk of secondary infection. We have identified human protein cystatin 9 (CST9) as a novel and effective immunotherapeutic approach to treat otherwise drug-resistant bacterial infections via modulation of pathogenic inflammation while promoting beneficial immune responses. Our proposal focuses on further evaluations of the human cysteine protease inhibitor CST9 and its development as a new therapeutic agent against pneumonia-related lung inflammation. Our findings showed the multifaceted immunoregulatory and antimicrobial functions of human recombinant (rCST9) whereby it modulated alveolar epithelial cell and macrophage inflammation, enhanced antibacterial immune responses to various Gram-negative pathogens, preserved lung integrity and directly interfered with bacterial pathogen replication. We hypothesize that rCST9 will modulate inflammation to combat lung damage and improve host survival in an experimental model of pneumonia caused by drug-resistant Delhi metallo-beta-lactamase-1 (NDM-1) producing Klebsiella pneumoniae (Kp). The objective and innovation of this proposal will be the optimization of rCST9 efficacy as a countermeasure against pneumonia (R21 phase) necessary for translation to drug development (R33 phase). We do not offer the opinion that rCST9 is a "magic bullet" for lung inflammatory diseases. But our data strongly support the diverse impacts of rCST9 on immune responses and pathogen virulence, making it ideally suited for more in-depth analyses as a promising therapeutic treatment (that may stand alone or be accompanied by additional therapeutic treatments) against pulmonary pathogens.