Synergy between the Host Immune System and Bacteriophage Is Essential for Successful Phage Therapy against an Acute Respiratory Pathogen
Synergy between the Host Immune System and Bacteriophage Is Essential for Successful Phage Therapy against an Acute Respiratory Pathogen
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DOI：
10.1016/j.chom.2017.06.018
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发表时间：
2017-07-12
影响因子：
30.3
通讯作者：
Debarbieux, Laurent
中科院分区：
文献类型：
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作者：
Roach, Dwayne R.;Leung, Chung Yin;Debarbieux, Laurent
多药耐药（MDR）细菌的出现激发了人们对噬菌体在治疗中的使用的新兴趣。然而，在动物宿主中有助于噬菌体介导的细菌清除的机制仍不清楚。我们在小鼠模型中研究了宿主免疫对噬菌体治疗MDR铜绿假单胞菌引起的急性肺炎的疗效的影响。在健康免疫活性、MyD 88缺陷、淋巴细胞缺陷和嗜中性粒细胞耗尽的小鼠宿主中比较噬菌体治疗性和预防性治疗的功效，揭示了嗜中性粒细胞-噬菌体协同作用对于肺炎的解决是必不可少的。体内结果的群体建模进一步表明，需要中性粒细胞来控制噬菌体敏感性和新出现的噬菌体耐药变体以清除感染。这种“免疫噬菌体协同作用”与噬菌体治疗成功主要是由于细菌对噬菌体杀伤的宽容的范例形成对比。最后，肺免疫效应细胞不能清除治疗性药物，肺组织对治疗性药物具有良好的免疫耐受性。
The rise of multi-drug-resistant (MDR) bacteria has spurred renewed interest in the use of bacteriophages in therapy. However, mechanisms contributing to phage-mediated bacterial clearance in an animal host remain unclear. We investigated the effects of host immunity on the efficacy of phage therapy for acute pneumonia caused by MDR Pseudomonas aeruginosa in a mouse model. Comparing efficacies of phage-curative and prophylactic treatments in healthy immunocompetent, MyD88-deficient, lymphocyte-deficient, and neutrophil-depleted murine hosts revealed that neutrophil-phage synergy is essential for the resolution of pneumonia. Population modeling of in vivo results further showed that neutrophils are required to control both phage-sensitive and emergent phage-resistant variants to clear infection. This "immunophage synergy'' contrasts with the paradigm that phage therapy success is largely due to bacterial permissiveness to phage killing. Lastly, therapeutic phages were not cleared by pulmonary immune effector cells and were immunologically well tolerated by lung tissues.