Department of Microbiology, Institut Pasteur, Paris 75015, France.
School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA; School of Physics, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Cell Host Microbe. 2017 Jul 12;22(1):38-47.e4. doi: 10.1016/j.chom.2017.06.018.
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.
耐药菌的出现重新激发了人们对噬菌体在治疗中的应用的兴趣。然而，在动物宿主中，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耐多药铜绿假单胞菌引起的急性肺炎的疗效的影响。比较噬菌体治疗和预防性治疗在健康免疫功能正常、MyD88 缺陷、淋巴细胞缺陷和中性粒细胞耗竭的小鼠宿主中的疗效，结果表明中性粒细胞-噬菌体协同作用对于肺炎的缓解是必不可少的。体内实验结果的群体建模进一步表明，中性粒细胞需要控制噬菌体敏感和新兴的噬菌体耐药变体，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归因于细菌对噬菌体杀伤的易感性这一范式形成对比。最后，治疗性噬菌体未被肺免疫效应细胞清除，并且在肺组织中具有良好的免疫耐受性。
