Kapoor Hannah, Maves Aaron M, Bowder Madeline A, Danelishvili Lia
Department of Biochemistry and Molecular Biology, College of Science, Oregon State University, Corvallis, OR, USA.
Department of Microbiology, College of Science, Oregon State University, Corvallis, OR, USA.
Sci Rep. 2025 Aug 5;15(1):28504. doi: 10.1038/s41598-025-07320-y.
The incidence of pulmonary infections caused by M. abscessus (MAB) is on rise globally. Despite susceptible infections, long-term, and combinational treatment, patients respond to MAB therapy only partially with low success rates. In recent years, therapeutic phages have been used in combination with antibiotics to enhance treatments for patients suffering with drug-resistant, chronic, and disseminated mycobacterial infections with favorable clinical outcomes. While phages are commonly recognized for their antimicrobial role through direct lysis of bacteria, expanding body of literature, describing phage interactions with the immune system, indicates that the therapeutic impact of phage may not solely hinge on lytic activity but also on stimulating innate immune responses. In this study, we aimed to uncover phages that work synergistically with macrophage cellular mechanisms, enhancing phagocyte-mediated reduction of intracellular MAB. We discovered phages stimulating TLR2 signaling associated with NLRP3 inflammasome activation, resulting in substantial attenuation of the intracellular pathogen growth. We also uncovered a new phenomenon of intracellular elimination of MAB through fusion of lytic phage vacuoles with bacterial phagosomes. This process is driven by a cellular mechanism triggered by phage exposure to phagocytic cells. New therapeutic characteristics of phage, described in this study, will contribute to future phage-based therapeutic interventions.
全球范围内，脓肿分枝杆菌（MAB）引起的肺部感染发病率正在上升。尽管采用了敏感感染、长期及联合治疗方法，但患者对MAB治疗的反应仅为部分有效，成功率较低。近年来，治疗性噬菌体已与抗生素联合使用，以增强对耐药、慢性和播散性分枝杆菌感染患者的治疗效果，并取得了良好的临床结果。虽然噬菌体通常因其通过直接裂解细菌发挥抗菌作用而被认可，但越来越多描述噬菌体与免疫系统相互作用的文献表明，噬菌体的治疗作用可能不仅取决于裂解活性，还取决于刺激先天免疫反应。在本研究中，我们旨在发现与巨噬细胞细胞机制协同作用的噬菌体，增强吞噬细胞介导的细胞内MAB减少。我们发现噬菌体刺激与NLRP3炎性小体激活相关的TLR2信号传导，导致细胞内病原体生长大幅减弱。我们还发现了溶菌噬菌体空泡与细菌吞噬体融合导致细胞内清除MAB的新现象。这一过程由噬菌体暴露于吞噬细胞触发的细胞机制驱动。本研究中描述的噬菌体新治疗特性将有助于未来基于噬菌体的治疗干预。
