The Innate Immune Response to Phages in Circulation
循环中噬菌体的先天免疫反应
Large numbers of phages are present in peripheral circulation and within tissues (4, 50). The pharmacokinetics of at least some of these phages are well characterized from studies performed to inform lytic phage therapy. Phages in circulation follow a temporal and spatial pattern of clearance independent of the route of administration. The lifetime of circulating phages is on the order of several days, with the largest decrease (>99%) within the first hour (55–60).
大量噬菌体存在于外周循环和组织内（4，50）。至少其中一些噬菌体的药代动力学特征已在为溶解性噬菌体疗法提供信息的研究中得到了很好的描述。循环中的噬菌体在时间和空间上的清除模式与给药途径无关。循环中噬菌体的寿命约为数天，在第一个小时内减少最多（>99%）（55-60）。
Following infusion, phages can be found in most major organs postcirculation with the highest and most persistent titers of phage in the liver and spleen (56, 61, 62), indicating these organs are a major route of clearance for circulating phage particles. Research on splenic and liver macrophages (Kupffer cells) suggests that these cells phagocytose phage rapidly and efficiently (58). The persistence of active phage in the liver is generally much lower than in the spleen (57, 62–64). Consistent with this, Kupffer cells are generally more effective at endocytosis and maintain higher basal reactive oxygen species (ROS) levels than splenic macrophages, and they express less proinflammatory cytokines in response to TLR ligation (65, 66). Internalized phage appeared to be processed and inactivated within phagolysosomes of these cells (67, 68).
输注后，噬菌体可在循环后的大多数主要器官中发现，其中肝脏和脾脏中的噬菌体滴度最高且最持久（56、61、62），这表明这些器官是循环噬菌体颗粒的主要清除途径。对脾脏和肝脏巨噬细胞（Kupffer 细胞）的研究表明，这些细胞能快速有效地吞噬噬菌体（58）。活性噬菌体在肝脏中的持久性通常比在脾脏中低得多（57，62-64）。与此相一致的是，与脾脏巨噬细胞相比，Kupffer 细胞的内吞作用通常更有效，并能维持较高的基础活性氧（ROS）水平，而且它们对 TLR 标记的反应中表达的促炎细胞因子较少（65、66）。内化的噬菌体似乎在这些细胞的吞噬溶酶体中被处理和灭活 ( 67, 68)。
Phage clearance is a two-step process whereby the vast majority of particles are rapidly eliminated in 24 h followed by slower clearance of the remaining ∼1% of circulating phages over the course of several days (58, 69). This slower tail may represent phages sequestered by antibodies or other components of the immune response. Inflammation and the presence of bacterial contaminants may also affect phage pharmacokinetics (70).
噬菌体的清除分为两个步骤，其中绝大多数颗粒会在 24 小时内被迅速清除，剩余的 1%循环噬菌体会在几天内被缓慢清除（58，69）。这种较慢的尾部清除可能是噬菌体被抗体或免疫反应的其他成分螯合。炎症和细菌污染物的存在也会影响噬菌体的药代动力学（70）。
Phages in circulation and within peripheral tissues are remarkably well tolerated immunologically. Phages found within sites of immune privilege, including the placenta (71) and the cerebrospinal fluid (CSF) (72), appear to be well tolerated as well. The recently sampled virome of CSF has confirmed that phage are present in relatively high abundance (104 pfu/mL) in the absence of inflammation (73). This is particularly notable when one considers phages typically are associated with lipopolysaccharide (LPS), bacterial DNA, and other potent immune stimulants. Infusion of phages for lytic phage therapy is likewise remarkably well tolerated, despite the presence of residual bacterial impurities.
血液循环中和外周组织中的噬菌体具有很好的免疫耐受性。在胎盘（71）和脑脊液（72）等免疫特权部位发现的噬菌体似乎也有很好的耐受性。最近对脑脊液病毒组的取样证实，在没有炎症的情况下，噬菌体的丰度相对较高（10 4 pfu/mL）（73）。如果考虑到噬菌体通常与脂多糖（LPS）、细菌 DNA 和其他强效免疫刺激剂相关联，这一点尤其值得注意。尽管存在残留的细菌杂质，但输注噬菌体进行溶解性噬菌体治疗的耐受性同样非常好。
It is likely that mechanisms exist to facilitate immune acceptance of large numbers of phages in circulation and within peripheral tissues. It may be, for example, that phage capsid proteins are adapted to mitigate immune recognition. Perhaps consistent with this, phages engineered to display peptides in the context of epitope discovery or phage vaccines are typically immunogenic, whereas lytic phage therapy is usually well tolerated. It may also be that clearance of phages from within the liver and spleen is linked to tolerogenic mechanisms. Both the liver and spleen house a significant reservoir of resident tolerogenic macrophages and dendritic cells (DCs) (74, 75). Finally, endogenous phages may be uniquely able to promote tolerogenic immune responses such as driving differentiation of M2 macrophages (76).
很可能存在一些机制来促进免疫系统接受血液循环和外周组织中的大量噬菌体。举例来说，噬菌体的外壳蛋白就可以减轻免疫识别。也许与此相一致，在表位发现或噬菌体疫苗的背景下，设计成显示肽的噬菌体通常具有免疫原性，而溶解性噬菌体疗法通常具有良好的耐受性。噬菌体在肝脏和脾脏内的清除也可能与耐受机制有关。肝脏和脾脏都有大量的常驻耐受性巨噬细胞和树突状细胞（DCs）（74，75）。最后，内源性噬菌体可能具有促进耐受性免疫反应的独特能力，如驱动 M2 巨噬细胞的分化 ( 76)。