Mechanisms of Phage–Host Immune System Interactions and Advances in Their Application in Antibacterial Therapy
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摘要: 抗生素滥用导致细菌耐药性问题日益严重，是全球公共卫生面临的重大威胁之一。噬菌体疗法是对抗细菌最有希望的生物疗法，它具有超越其抗菌特性的应用潜力，包括控制炎症、抗肿瘤应用、调节肠道微生物组以治疗特殊疾病等。但噬菌体自身存在免疫原性，治疗过程中噬菌体与宿主免疫系统相互作用会影响临床应用。本文概述了噬菌体疗法的应用进展和噬菌体疗法在应用过程中与人类宿主免疫系统的相互作用，包括先天免疫反应和适应性免疫反应，以期为噬菌体疗法的广泛应用提供理论指导。Abstract: The overuse of antibiotics has exacerbated bacterial antimicrobial resistance, which has become one of the major threats to global public health. Phage therapy is one of the most promising biological therapies for combating bacterial infections. In addition to its antibacterial activity, phage therapy has potential applications in inflammation control, antitumor application, and gut microbiome modulation for the treatment of specific diseases. However, bacteriophages are immunogenic, and their interactions with the host immune system during therapy may affect clinical application. This review summarizes advances in phage therapy and examines the interactions between bacteriophages and the human immune system during treatment, including both innate and adaptive immune responses, with the aim of providing a theoretical basis for the broader clinical application of phage therapy.
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Key words:
- Phage /
- Phage therapy /
- Innate immune response /
- Adaptive immune response
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图 1 噬菌体特异性抗体介导的清除路径图
A：被IgG结合的噬菌体经Fc受体被吞噬细胞识别并内化至吞噬溶酶体降解，加速噬菌体清除；B：IgG激活经典补体途径，C3b作为调理素被CR1受体识别，介导吞噬作用增强噬菌体清除，同时在空间上阻碍噬菌体对细菌的吸附；C：IgG结合噬菌体衣壳蛋白、鞘蛋白和尾丝蛋白，阻碍噬菌体吸附至细菌受体，导致细菌存活，噬菌体疗法失效。
Figure 1. Phage-specific antibody-mediated clearance pathways
图 2 噬菌体引发先天免疫反应
A：T4噬菌体的DNA被Toll样受体9识别后触发树突状细胞内的信号转导通路，促进多种细胞因子分泌；B：噬菌体感染细菌后暴露细菌部分抗原表位，激活经典补体途径，二者协同抗菌；C：噬菌体Ph17通过激活细胞表面Toll样受体2相关信号通路，激活吞噬细胞先天免疫防御、抑制脓肿分枝杆菌的免疫逃逸反应，被吞噬细胞吞噬后在吞噬细胞内杀灭脓肿分枝杆菌。
Figure 2. Bacteriophages elicit innate immune responses
图 3 噬菌体与补体系统的双刃剑效应
A：噬菌体降解细菌表面的荚膜多糖，促进MAC在细菌外膜上沉积，二者协同抗菌；B：C1q、C3b等补体蛋白附着于噬菌体表面，阻碍噬菌体对细菌的吸附，同时其调理作用促进吞噬细胞对噬菌体的吞噬。
Figure 3. The dual role of the complement system in bacteriophage clearance
图 4 不同免疫状态宿主噬菌体清除差异
A：免疫正常宿主中抗体、补体、吞噬细胞协同作用，快速清除噬菌体；B：补体缺陷宿主中补体调理作用受损，部分延迟清除；C：B细胞缺陷宿主中抗体缺失导致部分噬菌体清除延迟。
Figure 4. Differential phage clearance in hosts with varying immune statuses
图 5 噬菌体引发适应性免疫反应
A：噬菌体外源性抗原肽通过主要组织相容性复合体Ⅱ呈递给幼稚CD4+ T细胞，诱导体液免疫反应；B：一些噬菌体绕过T细胞，通过BCR直接与B细胞结合，诱导浆细胞分化，产生低亲和力IgM抗体；C：噬菌体内源性抗原肽呈递给与主要组织相容性复合体Ⅰ相关的幼稚CD8+ T细胞，刺激细胞毒性T淋巴细胞的分化，分泌穿孔素或颗粒酶诱导靶细胞凋亡，抑制噬菌体复制。
Figure 5. Bacteriophages elicit adaptive immune responses
图 6 噬菌体抗炎作用机制
A：噬菌体抑制巨噬细胞向M1型巨噬细胞极化，促进巨噬细胞向M2型巨噬细胞极化；B：噬菌体抑制细胞对细菌的吞噬作用减少ROS释放；C：噬菌体促进抗炎基因表达，抑制促炎基因的表达；D：类T4噬菌体尾部gp12蛋白与TLR4竞争结合LPS，阻断TLR4信号通路。
Figure 6. Mechanisms of the anti-inflammatory effects of bacteriophages
表 1 不同噬菌体疗法的代表性案例及应用效果
Table 1. Representative cases and application effects of different phage therapies
噬菌体疗法类型 代表性案例 噬菌体及相关制剂 应用效果 单噬菌体治疗 耐药假单胞菌感染且标准抗生素治疗无效的肺部囊性纤维化患者[14] 个体化单噬菌体制剂 成功治疗9名患者，治疗后痰液假单胞菌浓度降低，抗生素耐药性和毒力下降 单噬菌体治疗 耐药铜绿假单胞菌引起的慢性右髋假体感染，既往抗生素和手术治疗效果不佳[15] Pa53 成功治疗患者，截至2022年9月，患者临床状况良好，无复发感染 单噬菌体治疗 老年慢阻肺患者肺部耐药鲍曼不动杆菌感染，抗生素治疗效果不佳[16] Ab_SZ3 成功治疗患者，患者肺功能临床改善，截至2021年1月，患者无复发感染 噬菌体鸡尾酒治疗 高毒力耐药肺炎克雷伯氏菌感染小鼠模型[17] ΦK2044+ΦKR1+ΦKR8 噬菌体鸡尾酒较单噬菌体更有效清除生物膜，降低感染小鼠死亡率，并抑制噬菌体抗性菌产生 噬菌体鸡尾酒治疗 伴铜绿假单胞菌感染的囊性纤维化患者，开展首项人体1b/2a期随机、双盲、安慰剂对照试验[18] BMX-P1+BMX-P2+ BMX-P3 雾化吸入治疗后，患者痰液中铜绿假单胞菌检出量显著减少 噬菌体鸡尾酒治疗 脓肿分枝杆菌感染相关研究[19] ΦJabs+ΦJun14 噬菌体鸡尾酒较单噬菌体表现出更高杀菌能力，并抑制抗性菌产生 噬菌体联合抗生素治疗 涤纶主动脉弓假体术后铜绿假单胞菌感染，3年内多疗程抗生素治疗无效[20] OMKO1 成功治疗患者，治疗后铜绿假单胞菌对头孢他啶敏感性增加2倍，对环丙沙星敏感性增加10倍 噬菌体联合抗生素治疗 复杂耐甲氧西林金黄色葡萄球菌感染致硬膜外脓肿，9个月单纯抗生素治疗无效[21] 2种不同的金黄色葡萄球菌噬菌体+达巴万星 成功治疗患者，接受治疗2周脓血性分泌物逐渐减少至消失，13个月后痊愈出院 噬菌体联合抗生素治疗 耐药阿克罗莫杆菌感染的10岁肺部囊性纤维化女童22] Ax2CJ45φ2+氟氯唑沙星+美罗培南+瓦博巴坦 成功治疗患者，接受治疗后肺功能短期明显改善，治疗后8周和16周痰液均未分离出阿克罗莫杆菌 噬菌体联合抗生素治疗 耐甲氧西林金黄色葡萄球菌引起的膝关节和髋关节顽固性假体关节感染[23] SaWIQ0488ø1+达普托霉素 成功治疗患者，接受治疗3周后血培养未分离出MRSA，治疗后11个月无复发 噬菌体经过基因工程改造后应用 15岁肺部囊性纤维化伴播散性脓肿分枝杆菌感染患者，8年抗菌治疗无效并伴肺移植相关感染[24] 噬菌体Muddy+工程化裂解噬菌体衍生物ZoeJΔ45、BPsΔ33HTH-HRM10 成功治疗播散性脓肿分枝杆菌感染，是工程化噬菌体治疗的重要临床应用案例 噬菌体联合其他化学物质治疗 噬菌体与水凝胶联合制备噬菌体基抗菌水凝胶[25] 噬菌体基水凝胶制剂 提升局部治疗中的生物相容性和持续抗菌能力 噬菌体联合其他化学物质治疗 脂质体包封噬菌体用于增强胞内递送[26] 脂质体包封噬菌体 增强噬菌体进入巨噬细胞能力，同时保护其免受噬菌体特异性抗体影响 噬菌体联合其他化学物质治疗 噬菌体纳米载体递送，并可与抗生素联合[27] 纳米载体负载噬菌体 增强抗菌效果，并有望与抗生素产生协同作用 噬菌体联合其他化学物质治疗 噬菌体与抗菌肽或金属纳米颗粒联合[28] 噬菌体+抗菌肽/银纳米颗粒 提高对生物膜相关感染的抗菌潜力 
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