Phage therapy for treatment of virulent Klebsiella pneumoniae infection in a mouse model
Phage therapy for treatment of virulent Klebsiella pneumoniae infection in a mouse model
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噬菌体疗法用于治疗小鼠模型中强毒力肺炎克雷伯菌感染的研究
DOI：
10.1016/j.jgar.2019.09.018
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发表时间：
2020-06-01
影响因子：
4.6
通讯作者：
Tripathi, B. N.
中科院分区：
文献类型：
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作者：
Anand, Taruna;Virmani, Nitin;Tripathi, B. N.
目的：肺炎克雷伯菌是人类和动物的重要新发病原体，可导致严重的临床后果。抗生素使用的增加促进了耐碳青霉烯类和产生超广谱 β-内酰胺酶 (ESBL) 的肺炎克雷伯菌菌株的出现。最近，噬菌体疗法作为对抗新出现的抗菌药物耐药性的可能替代方案获得了发展势头。本研究旨在评估新型裂解噬菌体（VTCCBPA43）在肺炎小鼠模型中的治疗效果，以探讨噬菌体治疗对强毒性肺炎克雷伯菌感染的功效。方法：评估有尾噬菌体 VTCCBPA43 的生长动力学、体外宿主范围以及温度和 pH 敏感性。通过 SDS-PAGE 和 nLC-MS/MS 分析蛋白质成分。在 BALB/c 小鼠模型中，用强毒力肺炎克雷伯菌攻击 2 小时后观察治疗效果。结果：发现噬菌体 VTCCBPA43 具有高度耐受温度（高达 80 摄氏度）。它在 pH 5 时最活跃，爆发量为 172 PFU/mL，并且宿主范围较窄。通过鸟枪法蛋白质组学鉴定其为类KP36噬菌体。用强毒力肺炎克雷伯菌攻击后鼻内应用单剂量（2 x 10(9) PFU/小鼠）后，观察到体内生物活性噬菌体的存在以及所有时间点肺部细菌负荷的显着减少。病变严重程度的降低表明 VTCCBPA43 噬菌体疗法在肺炎小鼠模型中具有总体有益效果。结论：这项研究代表了通过鼻内途径有效噬菌体疗法对抗肺炎克雷伯菌感染的第一个体内证据。 (c) 2019 年国际抗菌化疗协会。由爱思唯尔有限公司出版
Objectives: Klebsiella pneumoniae is an important emerging pathogen of humans and animals leading to serious clinical consequences. Increased antibiotic use has promoted the emergence of carbapenem-resistant and extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae strains. Recently, phage therapy has gained momentum as a possible alternative against emerging antimicrobial resistance. This study was performed to assess the therapeutic effects of a novel lytic phage (VTCCBPA43) in a pneumonic mouse model in order to explore the efficacy of phage therapy against virulent K. pneumoniae infection.Methods: The tailed phage VTCCBPA43 was assessed for its growth kinetics, in vitro host range, and temperature and pH sensitivity. Protein constituents were analysed by SDS-PAGE and nLC-MS/MS. Therapeutic efficacy was observed 2 h post-challenge with virulent K. pneumoniae in a BALB/c mouse model.Results: Phage VTCCBPA43 was found to be highly temperature-tolerant (up to 80 degrees C). It was most active at pH 5, had a burst size of 172 PFU/mL and exhibited a narrow host range. It was identified as a KP36-like phage by shotgun proteomics. Following intranasal application of a single dose (2 x 10(9) PFU/mouse) post-challenge with virulent K. pneumoniae, the presence of biologically active phage in vivo and a significant reduction in the lung bacterial load at all time points was observed. A reduction in lesion severity suggested overall beneficial effects of VTCCBPA43 phage therapy in the pneumonic mouse model.Conclusion: This research represents the first in vivo evidence of effective phage therapy against K. pneumoniae infection by the intranasal route. (c) 2019 International Society for Antimicrobial Chemotherapy. Published by Elsevier Ltd.