THE MAMMALIAN PHAGEOME 哺乳动物噬菌体组
Phages are abundant within the human body. It is estimated that more than 1016 phages are present within each of us, outnumbering both our bacteria and our own cells (4). Most of these phages are present at sites of bacterial colonization, including the intestine (5), skin (6), urogenital tract (7), and upper respiratory tract (8).
噬菌体在人体内大量存在。据估计，我们每个人体内都有超过 10 个 16 噬菌体，其数量超过了我们的细菌和自身细胞（4）。这些噬菌体大多存在于细菌定植的部位，包括肠道（5）、皮肤（6）、泌尿生殖道（7）和上呼吸道（8）。
Despite great morphologic structural heterogeneity and genetic diversity (9), our phages share some common features that may be relevant to immune recognition. They are typically nonenveloped viruses, as the bacteria that produce them lack eukaryotic cell membranes. The majority characterized to date have DNA genomes [while RNA viruses are present in the gut, these are thought to be derived from ingested plant matter (10)]. Furthermore, these genomes typically have high deoxycytidylate-phosphate-deoxyguanylate (CpG) content, as with the bacteria that produce them.
尽管噬菌体具有很大的形态结构异质性和遗传多样性（9），但它们有一些共同特征，可能与免疫识别有关。它们通常是无包膜病毒，因为产生它们的细菌没有真核细胞膜。迄今表征的大多数噬菌体都有 DNA 基因组[虽然肠道中也有 RNA 病毒，但这些病毒被认为来自摄入的植物物质 ( 10)]。此外，这些基因组通常具有较高的脱氧胞苷酸-磷酸脱氧鸟苷酸（CpG）含量，与产生它们的细菌一样。
Phage life cycles exhibit several distinct patterns. Lytic or virulent phage production is synchronous with bacterial lysis and destruction, with progeny phages going on to infect new susceptible hosts. T4 produced by Escherichia coli is an example of a lytic phage. In contrast, lysogenic or temperate phages are passed on to daughter cells as prophages integrated within the bacterial genome or as plasmids. However, temperate phages also lyse their bacterial hosts opportunistically. λ phage also produced by E. coli is an example of a temperate phage. Finally, a subset of phages exhibit pseudolysogenic replication wherein phage progeny are released from the host bacterium without lysis. This type of life cycle is characteristic of filamentous phages in the Inoviridae family (e.g., Pseudomonas aeruginosa phage Pf or E. coli phages fd and M13) (11). Consistent with this more-benign mode of viral replication, many filamentous phages contribute to the fitness of their bacterial hosts via effects on toxin production, metabolism, and biofilm formation (12). Whether these distinctions between lytic, temperate, and pseudolysogenic phages affect direct phage-immune interactions is unclear and an important topic for future investigation.
噬菌体的生命周期呈现出几种不同的模式。溶解性或毒性噬菌体的产生与细菌的溶解和破坏同步，后代噬菌体继续感染新的易感宿主。大肠杆菌产生的 T4 就是溶解性噬菌体的一个例子。相比之下，溶解性噬菌体或温性噬菌体则以整合在细菌基因组中的原生噬菌体或质粒的形式传给子细胞。也由大肠杆菌产生的 λ 噬菌体就是温性噬菌体的一个例子。最后，有一部分噬菌体会进行假溶解复制，噬菌体的后代会从宿主细菌中释放出来，而不会被裂解。这种生命周期是猪病毒科丝状噬菌体的特征（如铜绿假单胞菌噬菌体 Pf 或大肠杆菌噬菌体 fd 和 M13）（11）。与这种较为温和的病毒复制模式相一致，许多丝状噬菌体通过影响毒素产生、新陈代谢和生物膜形成来提高细菌宿主的生存能力（12）。溶解性噬菌体、温和性噬菌体和假溶解性噬菌体之间的这些区别是否会影响噬菌体与免疫的直接相互作用尚不清楚，这也是未来研究的一个重要课题。
The gut microbiome produces the majority of phages in the body with up to 108 virus-like particles per milliliter in fecal filtrates (13). Phageome studies suggest that although extensive interpersonal variation is the norm, individual phage communities are highly temporally stable (14, 15). Indeed, it has been proposed that phages may contribute to the stability and resilience of the microbiome by promoting microbial diversity and serving as a repository of beneficial genetic material (5). Perhaps consistent with this, bacteriophage transfer was associated with successful outcomes of fecal transplant for Clostridium difficile colitis (16). Conversely, there are suggestions that the relative number, diversity, and composition of phages may be altered in inflammatory bowel disease (17), diabetes (18), and other disease settings (19). However, it is unclear whether the phageome contributes to or merely reflects shifts in the bacterial community associated with these states. The gut phageome is the topic of an excellent recent review (20).
肠道微生物群产生了人体内的大部分噬菌体，粪便滤液中每毫升可含有多达 10 个 8 病毒样颗粒（13）。噬菌体组研究表明，虽然人与人之间的差异很大，但单个噬菌体群落在时间上高度稳定（14、15）。事实上，有人提出，噬菌体可以通过促进微生物多样性和充当有益遗传物质的储存库，来促进微生物组的稳定性和恢复力（5）。噬菌体转移与艰难梭菌性结肠炎粪便移植的成功治疗结果有关（16）。相反，也有观点认为，在炎症性肠病（17）、糖尿病（18）和其他疾病（19）中，噬菌体的相对数量、多样性和组成可能会发生改变。然而，目前还不清楚噬菌体组是促成了还是仅仅反映了与这些状态相关的细菌群落的变化。肠道噬菌体组是近期一篇精彩综述的主题（20）。
INDIRECT EFFECTS OF PHAGES ON MAMMALIAN IMMUNITY
噬菌体对哺乳动物免疫的间接影响
Phages have well-established, important roles in bacterial pathogenesis, microbial ecology, and the genetic evolution of bacterial communities (21, 22). Phages thereby have clear, indirect effects on immune function and host defense. These are summarized in Figure 2.
噬菌体在细菌致病机理、微生物生态学和细菌群落遗传进化方面具有公认的重要作用 ( 21, 22)。因此，噬菌体对免疫功能和宿主防御有明显的间接影响。图 2 总结了这些影响。
图 2 噬菌体对哺乳动物免疫的间接影响。噬菌体遗传因子是细菌定植和入侵哺乳动物宿主的毒力因子。细菌表达噬菌体编码的蛋白质会增加上皮侵袭、粘附、抗生素耐药性和生物膜的形成，并抑制中性粒细胞的吞噬作用。相反，在粘膜层内积聚的噬菌体可能成为阻止细菌入侵的非宿主源性屏障。最后，噬菌体颗粒的转囊作用和顶端-基底转运可能是将大滴度噬菌体从进入部位（肠道、肺部、泌尿生殖系统）转入血液循环并最终扩散到全身的一种机制。图改编自 BioRender.com（2020 年）的肠道免疫系统（小肠），检索自 https://app.biorender.com/biorender-templates。
Phage-encoded proteins play important roles in bacterial virulence and human immunity. Lysogenic phages encode proteins that allow their bacterial hosts to invade the tissue barriers that form the first line of defense against bacterial pathogens. Perhaps the best known of these is cholera toxin, encoded by a temperate phage, Φctx, that parasitizes Vibrio cholerae (23). Other phage-derived virulence factors contribute to bacterial adhesion and colonization (24, 25), tissue invasion (26, 27), and biofilm formation (28).
噬菌体编码的蛋白质在细菌毒力和人体免疫中发挥着重要作用。溶菌性噬菌体编码的蛋白质能让细菌宿主侵入组织屏障，而组织屏障是抵御细菌病原体的第一道防线。其中最著名的可能是霍乱毒素，它由一种寄生于霍乱弧菌的温带噬菌体Φctx编码（23）。其他噬菌体衍生的毒力因子有助于细菌的粘附和定植（24、25）、组织侵袭（26、27）以及生物膜的形成（28）。
Phage-encoded proteins eliminate or deter phagocytes that otherwise would mediate immune clearance. For example, chemotaxis inhibitory protein of Staphylococcus aureus is a phage-encoded protein that binds and attenuates the activity of the neutrophil receptors for complement and formylated proteins, thereby protecting S. aureus from neutrophil-mediated killing (29). Other phage-encoded proteins are involved in exotoxin production or delivery (30), cytotoxicity (31), intracellular infection (32), and superantigen production (33).
噬菌体编码的蛋白质会消除或阻止吞噬细胞，否则吞噬细胞就会介导免疫清除。例如，金黄色葡萄球菌的趋化抑制蛋白是一种噬菌体编码蛋白，它能结合并削弱中性粒细胞受体对补体和甲酰化蛋白的活性，从而保护金黄色葡萄球菌免受中性粒细胞介导的杀灭（29）。其他噬菌体编码蛋白参与外毒素的产生或传递（30）、细胞毒性（31）、细胞内感染（32）和超抗原的产生（33）。
Most of these phage-encoded virulence genes are regulated by chromosomally expressed transcription factors (34–36) and are produced during lysogeny, when other phage-encoded genes are not being actively transcribed. For example, the λ-encoded bor of E. coli and the phage-encoded vir of Mycoplasma arthritidis lie on the noncoding strand relative to the lytic phage genes (37). Finally, phages promote horizontal spread of antibiotic resistance genes both within and between bacterial strains (38, 39).
这些噬菌体编码的毒力基因大多由染色体表达的转录因子（34-36）调控，并在溶菌过程中产生，此时其他噬菌体编码的基因并没有被积极转录。例如，大肠杆菌的λ编码bor和关节支原体的噬菌体编码vir位于非编码链上，而溶菌体基因则位于非编码链上（37）。最后，噬菌体可促进抗生素耐药性基因在细菌菌株内部和菌株之间的水平传播 ( 38, 39)。
In these ways, prophages contribute to the fitness of their bacterial hosts and increase the likelihood of their own propagation. Prophages can also lose genes, including those necessary for virion production, which leads to their domestication (40, 41). These resulting prophage-derived genomic elements can be selectively maintained when they still confer some advantage (40, 42). Many phage-bacteria interactions thereby transcend simple parasitism and instead are intricate examples of coevolution.
通过这些方式，噬菌体可以提高细菌宿主的适应能力，增加自身繁殖的可能性。噬菌体也会丢失基因，包括产生病毒所需的基因，从而导致其驯化（40，41）。当这些噬菌体产生的基因组元件仍然具有某种优势时，它们就会被选择性地保留下来（40，42）。因此，许多噬菌体与细菌的相互作用超越了简单的寄生关系，而是共同进化的复杂例子。