The contribution of neutrophils to bacteriophage clearance and pharmacokinetics in vivo.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-10-22 DOI:10.1172/jci.insight.181309
Arne Echterhof, Tejas Dharmaraj, Arya Khosravi, Robert McBride, Lynn Miesel, Ju-Hsin Chia, Patrick M Blankenberg, Kun-Yuan Lin, Chien-Chang Shen, Yu-Ling Lee, Yu-Chuan Yeh, Wei Ting Liao, Francis G Blankenberg, Krystyna Dąbrowska, Derek F Amanatullah, Adam R Frymoyer, Paul L Bollyky
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Abstract

With the increasing prevalence of antimicrobial-resistant bacterial infections, there is interest in using bacteriophages (phages) to treat such infections. However, the factors that govern bacteriophage pharmacokinetics in vivo remain poorly understood. Here, we have examined the contribution of neutrophils, the most abundant phagocytes in the body, to the pharmacokinetics of i.v. administered bacteriophage in uninfected mice. A single dose of LPS-5, a bacteriophage recently used in human clinical trials to treat drug-resistant Pseudomonas aeruginosa, was administered i.v. to both immunocompetent BALB/c and neutropenic CD1 mice. Phage concentrations were assessed in peripheral blood and spleen at 0.25, 1, 2, 4, 8, 12, and 24 hours after administration by plaque assay and qPCR. We observed that the phage clearance was only minimally affected by neutropenia. Indeed, the half-lives of phages in blood in BALB/c and CD1 mice were 3.45 and 3.66 hours, respectively. These data suggest that neutrophil-mediated phagocytosis is not a major determinant of phage clearance. Conversely, we observed a substantial discrepancy in circulating phage levels over time when measured by qPCR versus plaque assay, suggesting that significant inactivation of circulating phages occurs over time. These data indicate that alternative factors, but not neutrophils, inactivate i.v. administered phages.

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中性粒细胞对体内噬菌体清除和药代动力学的贡献
随着耐抗菌细菌感染的日益流行,人们对使用噬菌体(噬菌体)治疗此类感染产生了兴趣。然而,人们对影响噬菌体体内药代动力学的因素仍然知之甚少。在这里,我们研究了嗜中性粒细胞(人体内数量最多的吞噬细胞)对未感染小鼠静脉注射噬菌体药代动力学的影响。对免疫功能正常的 BALB/c 小鼠和中性粒细胞增多的 CD1 小鼠静脉注射单剂量 LPS-5,这是一种最近用于人类临床试验治疗耐药铜绿假单胞菌的噬菌体。在给药后 0.25、1、2、4、8、12 和 24 小时,通过斑块检测和 qPCR 评估外周血和脾脏中的噬菌体浓度。我们观察到,噬菌体清除率受中性粒细胞减少症的影响很小。事实上,噬菌体在 BALB/c 和 CD1 小鼠血液中的半衰期分别为 3.45 和 3.66 小时。这些数据表明,中性粒细胞介导的吞噬作用并不是噬菌体清除的主要决定因素。相反,我们观察到通过 qPCR 与斑块检测法测量的循环噬菌体水平随着时间的推移存在很大差异,这表明循环噬菌体会随着时间的推移发生显著失活。这些数据表明,替代因子而非中性粒细胞会使静脉注射的噬菌体失活。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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