INNATE IMMUNITY AND DIRECT INTERACTIONS WITH PHAGES
先天性免疫和与噬菌体的直接相互作用
Innate immunity involves structural and germline-encoded features that govern the interface between our microbial and human selves. Phages both traverse and contribute to these barriers and may play a central role in our relationship with bacterial flora. These interactions take place at several sites, including the mucosa, in circulation, and within cells, and involve recognition of phages on the cell surface and within endocytic vesicles.
先天性免疫涉及结构和种系编码特征，这些特征控制着微生物与人类自身之间的界面。噬菌体既能穿越这些屏障，也能为这些屏障做出贡献，并可能在我们与细菌菌群的关系中发挥核心作用。这些相互作用发生在多个部位，包括粘膜、血液循环和细胞内，涉及识别细胞表面和细胞内囊泡中的噬菌体。
Phages and Mucosal Immunity
噬菌体与粘膜免疫
Phages are abundant at sites of bacterial colonization and may directly contribute to barrier defenses at the mucosal interface. Barr et al. (43) demonstrated that mucosal surfaces retain populations of adherent phages on their surface of up to 109 phages per biopsy. Phages may be adapted to facilitate these interactions. E. coli T4 phage possesses immunoglobulin (Ig)-like domains on capsid proteins that interact with mucins and surface glycoproteins on epithelial cells (43). Similar Ig superfamily-like protein domains are present in a wide variety of phage families, suggesting potential widespread enrichment of other phages within mucosal layers (44, 45). Mucosal binding was shown to enhance the susceptibility of some bacteria to phage-mediated lysis (46) and to promote more efficient diffusion of phages within the mucus layer (47). Phages within the mucosal tissue may thereby serve as a ubiquitous, strain-specific, and non-host-derived barrier to bacterial invasion (43, 46). These data point to a complex interplay between phages, bacteria, and mucosal surfaces that awaits further exploration. Among other open questions, it would be important to know if antiphage antibodies compromise or modify this form of barrier immunity.
噬菌体在细菌定植部位大量存在，可直接促进粘膜界面的屏障防御功能。Barr 等人（43）证实，粘膜表面保留的附着噬菌体数量高达 10 9 个。噬菌体可能会适应这些相互作用。大肠杆菌 T4 噬菌体的噬菌体蛋白上有类似免疫球蛋白（Ig）的结构域，能与上皮细胞的粘蛋白和表面糖蛋白相互作用（43）。各种噬菌体家族中都有类似的 Ig 超家族样蛋白结构域，这表明其他噬菌体可能在粘膜层中广泛富集（44、45）。研究表明，粘膜结合可提高某些细菌对噬菌体介导的裂解的敏感性（46），并促进噬菌体在粘液层内更有效的扩散（47）。因此，粘膜组织内的噬菌体可作为一种无处不在的、菌株特异性的和非宿主衍生的细菌入侵屏障（43、46）。这些数据表明，噬菌体、细菌和粘膜表面之间存在复杂的相互作用，有待进一步探索。除其他未决问题外，了解抗噬菌体抗体是否会损害或改变这种屏障免疫形式也很重要。
The intestinal virome is reported to influence outcomes in mouse models of colitis, and phage effects on innate immunity may contribute to this. Yang et al. (48) reported that a cocktail of antiviral drugs aggravated dextran sulfate sodium (DSS)-induced colitis in mice while gut resident viruses recognized by Toll-like receptor (TLR) 3 and TLR7 were protective via a mechanism involving production of interferon (IFN)-β. However, while phages comprise much of the intestinal virome, this study did not specifically focus on the role of phages. Conversely, Gogokhia et al. (49) reported that oral administration of a phage cocktail aggravated DSS colitis in a TLR9-dependent manner. Additional research is needed to clarify the role of phages in intestinal homeostasis.
据报道，肠道病毒群会影响小鼠结肠炎模型的结果，而噬菌体对先天性免疫的影响可能是其中的一个原因。Yang等人（48）报告说，鸡尾酒抗病毒药物会加重右旋糖酐硫酸钠（DSS）诱导的小鼠结肠炎，而通过Toll样受体（TLR）3和TLR7识别的肠道常驻病毒会通过产生干扰素（IFN）-β的机制起到保护作用。不过，虽然噬菌体在肠道病毒组中占很大比例，但这项研究并没有特别关注噬菌体的作用。相反，Gogokhia 等人 ( 49) 报道称，口服噬菌体鸡尾酒会以 TLR9 依赖性方式加重 DSS 结肠炎。要明确噬菌体在肠道稳态中的作用，还需要更多的研究。
The influence of mucosal-associated phages may extend far beyond the epithelial interface. Large numbers of phages translocate across the human gut and into systemic circulation via transcytosis across cells with a potential role for paracytosis at sites of inflammation. This transit has been estimated to occur at a rate of 3.1 × 107 particles/day, based on in vitro studies of cell monolayers (4, 50). For phage T4 this uptake occurs in an apical-to-basolateral direction via transcytosis through the Golgi apparatus (4). Particular phages may be taken up more readily (51), and particular peptide sequences may facilitate this transit (52). T1 phage introduced directly into the small intestine was shown to enter gut-draining lymph and blood (53). Circulating phages retain bioactivity against bacteria (54), and this might conceivably contribute to host defense against bacteria that likewise enter the bloodstream.
粘膜相关噬菌体的影响可能远远超出上皮界面。大量噬菌体穿过人体肠道，通过细胞间的转运作用进入全身血液循环，并在炎症部位发挥潜在的副吞噬作用。根据细胞单层体外研究（4、50），这种转运的速度估计为 3.1 × 10 7 粒子/天。对于噬菌体 T4 而言，这种吸收是通过高尔基体的转囊作用，以从顶端到基底侧的方向进行的（4）。特定的噬菌体可能更容易被吸收（51），而特定的肽序列可能会促进这种转运（52）。研究表明，直接引入小肠的 T1 噬菌体可以进入肠道排泄的淋巴和血液（53）。循环中的噬菌体对细菌具有生物活性（54），可以想象，这可能有助于宿主抵御同样进入血液的细菌。
These studies highlight both the potential importance of phage interactions with mucosal immunity and how little we know about this topic at present. For example, it is unclear how many phages traverse across mucosal tissues, what mechanisms are involved, whether cells with dedicated roles in sensing the intestinal environment (e.g., M cells) facilitate this, or whether inflammation affects this transit.
这些研究既凸显了噬菌体与粘膜免疫相互作用的潜在重要性，也说明我们目前对这一主题知之甚少。例如，目前还不清楚有多少噬菌体穿过粘膜组织，其中涉及哪些机制，专门负责感知肠道环境的细胞（如 M 细胞）是否促进了这一过程，或者炎症是否会影响这种转运。