Phage–Phagocyte Interaction
噬菌体与吞噬细胞的相互作用
A phage selected for phage therapy should be resistant to phagosomal degradation, to avoid or delay the induction of the phage’s specific adaptive immunity response and extend the survival of the phage in immunocompetent individuals.17,18 Therapeutic phages are naturally immunogenic, so they stimulate complex interactions between innate and adaptive immune cells that may affect the phage therapy. Bacterial elimination occurs owing to stimulation of local immune responses as a result of phage and bacterial-derived pathogen-associated molecular patterns (PAMPs). Since phages are immunogenic, they induce phage-specific humoral memory, which can hamper their therapeutic success owing to neutralization.19
被选作噬菌体疗法的噬菌体应能抵抗噬菌体降解，以避免或延缓诱导噬菌体的特异性适应性免疫反应，延长噬菌体在免疫功能正常个体中的存活时间。治疗性噬菌体具有天然的免疫原性，因此会激发先天性免疫细胞和适应性免疫细胞之间复杂的相互作用，从而影响噬菌体疗法。噬菌体和细菌衍生的病原体相关分子模式（PAMPs）会刺激局部免疫反应，从而消灭细菌。由于噬菌体具有免疫原性，它们会诱导噬菌体特异性体液记忆，这可能会因中和作用而影响治疗效果。 19
The role of phagocytic cells is to recognize and eliminate foreign antigens and to activate the adaptive immune system response whenever necessary. Leukocytes bind to phages in a time-, concentration-, and temperature-dependent manner, and endocytose them (through phagocytosis for particles >500 nM) to remove them. Polymorphonuclear leukocytes and macrophages can degrade phages, and phage degradation is the first step in stimulating antigen presentation and the development of an adaptive immune response.19,20 When phages express proteins that mediate bacteria–phage interaction, they bind together and macrophages become activated. Macrophages phagocytose extracellular bacteria and endocytose the phages along with them. Phagocytosis is stimulated via bacteria and phage-derived PAMPs and continual phagocytosis of phage-infected bacteria occurs. Bacteria and phage-derived PAMPs again co-stimulate macrophage activity.21,22 Antibodies produced against the bacteria opsonize the bacteria and facilitate phagocytosis by macrophages, which promotes bacterial clearance. Phage–antibody complexes bind to Fc receptors on macrophages, which triggers endocytosis and subsequent phage clearance.
吞噬细胞的作用是识别和清除外来抗原，并在必要时激活适应性免疫系统反应。白细胞以时间、浓度和温度依赖的方式与噬菌体结合，并内吞噬菌体（对于大于 500 nM 的微粒，则通过吞噬作用）将其清除。多形核白细胞和巨噬细胞可以降解噬菌体，而噬菌体降解是刺激抗原递呈和产生适应性免疫反应的第一步。当噬菌体表达介导细菌与巨噬细胞相互作用的蛋白质时，它们就会结合在一起，巨噬细胞就会被激活。巨噬细胞吞噬细胞外的细菌，并将噬菌体一起内吞。噬菌体通过细菌和噬菌体衍生的 PAMPs 刺激吞噬作用，并不断吞噬受噬菌体感染的细菌。细菌和噬菌体衍生的 PAMPs 再次共同刺激巨噬细胞的活性。 21 22 针对细菌产生的抗体会对细菌产生疏松作用，并促进巨噬细胞的吞噬作用，从而促进细菌的清除。噬菌体-抗体复合物与巨噬细胞上的 Fc 受体结合，引发内吞作用，进而清除噬菌体。
In general, for phage therapy to be effective there must be a strong interaction between host-derived ligands and host pattern recognition receptors. Unfortunately, weak pattern recognition receptor activation in immune-deficient individuals affects the individual innate immune response. Thus, clinical studies need to be conducted by enrolling individuals with different immune deficiency states to apply phage therapy.
一般来说，要使噬菌体疗法有效，宿主衍生配体与宿主模式识别受体之间必须有很强的相互作用。遗憾的是，免疫缺陷患者的模式识别受体激活能力较弱，会影响个体的先天性免疫反应。因此，临床研究需要招募不同免疫缺陷状态的个体来应用噬菌体疗法。
Phage–Adaptive Immune System Interaction
噬菌体与自适应免疫系统的相互作用
Phages strongly influence adaptive immunity via their effects on humeral immunity and effector polarization. They modulate the immune response and have a profound effect on the outcome of bacterial infection.23 Individuals exposed to phage therapy or naturally existing phages will clearly develop antibodies because phages are composed of densely packed immunogenic DNA or RNA and a protein coat.22,24
噬菌体通过对体液免疫和效应极化的影响，对适应性免疫产生强烈的影响。它们能调节免疫反应，并对细菌感染的结果产生深远影响。 23 接触噬菌体疗法或天然存在的噬菌体的人显然会产生抗体，因为噬菌体是由致密的免疫原 DNA 或 RNA 和蛋白外衣组成的。 22 24
Phages alone are not sufficient to fight bacterial infection. The combined effect of the immune system along with phage therapy is essential to fight bacterial infections. Phages are themselves immunogenic microbes which can activate the human adaptive immune system. Phage-mediated bacterial lysis stimulates the human adaptive immune response, which enhances the efficacy of phage therapy. However, adverse phage treatment may cause toxicity owing to the release of endotoxins as a result of bacterial lysis.19,25
单靠噬菌体不足以对抗细菌感染。免疫系统与噬菌体疗法的共同作用对抗击细菌感染至关重要。噬菌体本身就是免疫原微生物，可以激活人体的适应性免疫系统。噬菌体介导的细菌裂解可刺激人体适应性免疫反应，从而提高噬菌体疗法的疗效。然而，由于细菌裂解会释放内毒素，噬菌体治疗的不良反应可能会导致中毒。 19 25
Phage–immune interactions depend on immune recognition through pattern recognition receptors, the immunogenic nature of the phage, and the multiplication rate of the phage. The pattern recognition receptor recruits phagocytes to the site of infection to resolve the infection. It recognizes phage-derived DNA and RNA, resulting in phage-mediated activation of innate immune cells. The commitment of the pattern recognition receptor and the level of immune activation depend on phage type, phage dose, and nucleic acid synthesis activity.26,27 Phages are normally immunogic in nature. So, to evade host immune response, repeated administration of phages is required to clear bacterial infection. Therefore, immunogenicity should be considered before phages are used for therapy.28 Phages were widely administered intravenously decades ago to diagnose and monitor primary and secondary immunodeficiency without reported complications even in patients with prolonged phage survival in their bloodstream. This implies their inherently low toxic effect.46 Fifty healthy volunteers who were not involved in phage therapy or in phage work were evaluated for anti-phage antibody production against phage T4, and they were positive for the naturally occurring phage antibody.22 A remarkable decline in phage activity was observed in 81% of participants seropositive for the phage antibody. In these positive sera, natural IgG antibodies specific to the phage proteins gp23*gp24*Hoc and Soc were identified. These findings show that anti-T4 phage antibodies are frequent in the human population.47 The multiplication rate of phages can be reduced by IgG or IgA. Phages can be removed from the human body by high antibody levels and the Fc receptor-mediated uptake of phage/antibody complexes by macrophages. One of the drawbacks of phage therapy is that phages are immunogenic, so that antibodies are produced against them, which neutralize the phages and hinder infection of a bacterium by phages.19 At present, there is a knowledge gap on whether this regulatory function of anti-phage antibodies can prevent the appearance of resistance to phages and pre-existing immunity to natural phages, affecting phage therapy. More importantly, it is not known which phage-specific factors are responsible for the mechanism of phage clearance.29 To evade adaptive humeral immunity, further work on phage modification, to remove their immunogenicity and retain their lytic effect, is required.
噬菌体-免疫相互作用取决于通过模式识别受体进行的免疫识别、噬菌体的免疫原性以及噬菌体的繁殖率。模式识别受体将吞噬细胞吸引到感染部位，以解决感染问题。它能识别噬菌体衍生的 DNA 和 RNA，从而激活噬菌体介导的先天性免疫细胞。模式识别受体的承诺和免疫激活水平取决于噬菌体类型、噬菌体剂量和核酸合成活性。噬菌体通常具有免疫性质。因此，为了逃避宿主的免疫反应，需要反复使用噬菌体来清除细菌感染。因此，在将噬菌体用于治疗前应考虑免疫原性。 28 几十年前，噬菌体被广泛用于静脉注射，以诊断和监测原发性和继发性免疫缺陷，即使噬菌体在血液中存活时间较长的患者也没有出现并发症的报道。这说明噬菌体本身毒性很低。 46 对 50 名未参与噬菌体治疗或噬菌体工作的健康志愿者进行了抗噬菌体 T4 抗体产生情况的评估，结果显示他们的天然噬菌体抗体呈阳性。 22 在噬菌体抗体血清阳性的参与者中，81% 的人的噬菌体活性明显下降。在这些阳性血清中，发现了特异于噬菌体蛋白 gp23*gp24*Hoc 和 Soc 的天然 IgG 抗体。这些发现表明，抗 T4 噬菌体抗体在人类中很常见。 47 IgG 或 IgA 可以降低噬菌体的繁殖率。噬菌体可通过高抗体水平和巨噬细胞摄取噬菌体/抗体复合物的 Fc 受体介导从人体内清除。噬菌体疗法的缺点之一是噬菌体具有免疫原性，因此会产生针对噬菌体的抗体，从而中和噬菌体，阻碍噬菌体感染细菌。 19 目前，抗噬菌体抗体的这种调节功能能否防止出现对噬菌体的抗药性和对天然噬菌体的原有免疫力，从而影响噬菌体疗法，还是一个知识空白。更重要的是，噬菌体清除机制是由哪些噬菌体特异性因素造成的尚不清楚。 29 为了规避适应性体液免疫，需要进一步研究噬菌体的修饰，以消除其免疫原性并保留其溶解作用。