对于许多病原体而言，其进入宿主的初始点是粘膜上皮细胞，而宿主的免疫系统会在这一表面部署若干个防御机制，包括黏液自身。如今，Barr等人指出，噬菌体或许会在宿主的粘膜表面构成一个额外的抗菌防御机制。
作者对一系列生物体的粘膜表面进行了采样，并且发现，与周围环境相比，噬菌体与细菌的比例在这些表面上大约是前者的4倍。对粘附在人类细胞系上的噬菌体T4进行的检测表明，与不生成黏液的细胞相比，会有更多的噬菌体粘附在产生黏液的细胞上，并且黏液的化学移除会减少噬菌体的粘附。
人体肠道中的许多噬菌体会用高变免疫球蛋白（Ig）样域——与许多生物体中的细胞粘附有关——编码蛋白质。T4表面蛋白质Hoc（具有高度抗原性外衣壳）包含有4个这样的域，作者推测它们可能会结合黏液的成分。事实上，与一种缺乏Hoc的突变体相比，粘附在涂抹了粘蛋白的琼脂上的T4噬菌体相对于没有涂抹琼脂的T4噬菌体的数量的增加，对于野生型噬菌体而言是非常大的。此外，作者发现，尽管野生型T4能够结合不同的哺乳动物多糖，但它对于这些通常发现于粘蛋白糖蛋白中的多糖具有一种特别的亲和力，而Hoc缺乏的噬菌体则在所有610种多糖测试中表现出了有限的结合能力。因此，噬菌体T4似乎能够通过Hoc与粘蛋白多糖的互动粘附于黏液上。
溶解性噬菌体，例如T4，杀死了与它们的寄助株竞争的菌株。为了测试是否这样的溶解性活动能够减少粘膜表面的细菌定植，作者评估了暴露在粘膜生成组织培养细胞——已用噬菌体T4进行了预处理——中的大肠杆菌的影响。与没用进行预处理的细胞相比，细菌粘附和生皮细胞死亡在T4预处理的细胞中都显着减少，意味着噬菌体对生皮细胞具有一种保护效应。
基于这些发现，Barr等人提出了一个模式，即溶解性噬菌体通过蛋白质表面的Ig-样域结合粘蛋白的多糖成分，从而利用细菌形成了一个能够减少黏液定植的抗菌层，并因此保护下面的生皮细胞免遭感染。他们进一步提出，Ig-样域的超突变以及黏液的动力学属性——不但在结构中变化，同时也不断在外表面蜕化——将使得噬菌体能够快速适应黏液及细菌入侵的变化。
这种模式在肠道环境中的关联性，及其是否适用于温和噬菌体（在肠道中很常见）依然有待观察，并且在治疗开发上的潜力，例如噬菌体调节的免疫力，依然需要探索。这一发现毫无疑问将成为未来许多关键发现的跳板。（生物谷Bioon.com）
生物谷推荐英文摘要：
Nature Reviews Microbiology doi:10.1038/nrmicro3064
A new barrier at mucosal surfaces
Lucie Wootton
For many pathogens, the initial point of entry into the host is the mucosal epithelium, and the host immune system deploys several defence mechanisms at this surface, including the mucus itself. Now, Barr et al. show that phages might constitute an additional antibacterial defence mechanism at host mucosal surfaces.
The authors sampled mucosal surfaces from a range of organisms and found that the phage-to-bacterium ratio was about four-fold higher at these surfaces than in neighbouring environments. Testing phage T4 adherence to human cell lines showed that more phages adhered to mucus-producing cells than to non-mucus-producing cells and that chemical removal of the mucus reduced phage adherence.
Many phages in the human intestine encode proteins with hypervariable immunoglobulin (Ig)-like domains, which are involved in cell adhesion in many organisms. The T4 surface protein Hoc (highly antigenic outer capsid) contains four such domains, which the authors speculated might bind mucus components. Indeed, the increase in the number of T4 phages adhering to mucin-coated agar compared with non-coated agar was considerably greater for wild-type phages than for a Hoc-deficient mutant. Moreover, the authors found that although wild-type T4 could bind diverse mammalian glycans, it had a particular affinity for those commonly found in mucin glycoproteins, whereas the Hoc-deficient phage displayed limited binding to all 610 glycans tested. Thus, phage T4 seems to adhere to mucus through the interaction of Hoc with mucin glycans.
Lytic phages such as T4 kill bacterial strains that compete with their host strain. To test whether such lytic activity could reduce bacterial colonization at mucosal surfaces, the authors assessed the effects of Escherichia coli exposure on mucus-producing tissue culture cells that had been pre-treated with phage T4. Both bacterial attachment and epithelial cell death were significantly lower for T4-treated cells than for non-treated cells, indicating that the phage had a protective effect on the epithelium.
On the basis of these findings, Barr et al. present a model in which lytic phages bind glycan components of mucin through the Ig-like domains of surface proteins, forming an antimicrobial layer that decreases mucus colonization by bacteria and thus protects the underlying epithelial cells from infection. They further propose that the hypervariability of the Ig-like domains and the dynamic nature of the mucus, which is not only variable in structure but also continually sloughed off at the outer surface, would allow rapid phage adaptation to both changes in the mucus and bacterial invasion.
The relevance of this model in the gut environment and whether it applies to temperate phages (which are common in the gut) remain to be seen, and the potential to therapeutically exploit such phage-mediated immunity also needs to be explored. This work will undoubtedly be a spring-board to many key discoveries in the future.
