對(duì)于許多病原體而言,，其進(jìn)入宿主的初始點(diǎn)是粘膜上皮細(xì)胞,，而宿主的免疫系統(tǒng)會(huì)在這一表面部署若干個(gè)防御機(jī)制，包括黏液自身,。如今,，Barr等人指出，噬菌體或許會(huì)在宿主的粘膜表面構(gòu)成一個(gè)額外的抗菌防御機(jī)制,。
作者對(duì)一系列生物體的粘膜表面進(jìn)行了采樣,，并且發(fā)現(xiàn)，與周圍環(huán)境相比,，噬菌體與細(xì)菌的比例在這些表面上大約是前者的4倍,。對(duì)粘附在人類細(xì)胞系上的噬菌體T4進(jìn)行的檢測(cè)表明，與不生成黏液的細(xì)胞相比,，會(huì)有更多的噬菌體粘附在產(chǎn)生黏液的細(xì)胞上,，并且黏液的化學(xué)移除會(huì)減少噬菌體的粘附。
人體腸道中的許多噬菌體會(huì)用高變免疫球蛋白（Ig）樣域——與許多生物體中的細(xì)胞粘附有關(guān)——編碼蛋白質(zhì),。T4表面蛋白質(zhì)Hoc（具有高度抗原性外衣殼）包含有4個(gè)這樣的域,，作者推測(cè)它們可能會(huì)結(jié)合黏液的成分。事實(shí)上,，與一種缺乏Hoc的突變體相比,，粘附在涂抹了粘蛋白的瓊脂上的T4噬菌體相對(duì)于沒(méi)有涂抹瓊脂的T4噬菌體的數(shù)量的增加，對(duì)于野生型噬菌體而言是非常大的,。此外,，作者發(fā)現(xiàn)，盡管野生型T4能夠結(jié)合不同的哺乳動(dòng)物多糖,，但它對(duì)于這些通常發(fā)現(xiàn)于粘蛋白糖蛋白中的多糖具有一種特別的親和力,，而Hoc缺乏的噬菌體則在所有610種多糖測(cè)試中表現(xiàn)出了有限的結(jié)合能力。因此,，噬菌體T4似乎能夠通過(guò)Hoc與粘蛋白多糖的互動(dòng)粘附于黏液上,。
溶解性噬菌體，例如T4,，殺死了與它們的寄助株競(jìng)爭(zhēng)的菌株。為了測(cè)試是否這樣的溶解性活動(dòng)能夠減少粘膜表面的細(xì)菌定植,，作者評(píng)估了暴露在粘膜生成組織培養(yǎng)細(xì)胞——已用噬菌體T4進(jìn)行了預(yù)處理——中的大腸桿菌的影響,。與沒(méi)用進(jìn)行預(yù)處理的細(xì)胞相比，細(xì)菌粘附和生皮細(xì)胞死亡在T4預(yù)處理的細(xì)胞中都顯著減少,，意味著噬菌體對(duì)生皮細(xì)胞具有一種保護(hù)效應(yīng),。
基于這些發(fā)現(xiàn)，Barr等人提出了一個(gè)模式,，即溶解性噬菌體通過(guò)蛋白質(zhì)表面的Ig-樣域結(jié)合粘蛋白的多糖成分,，從而利用細(xì)菌形成了一個(gè)能夠減少黏液定植的抗菌層,，并因此保護(hù)下面的生皮細(xì)胞免遭感染。他們進(jìn)一步提出,，Ig-樣域的超突變以及黏液的動(dòng)力學(xué)屬性——不但在結(jié)構(gòu)中變化,，同時(shí)也不斷在外表面蛻化——將使得噬菌體能夠快速適應(yīng)黏液及細(xì)菌入侵的變化。
這種模式在腸道環(huán)境中的關(guān)聯(lián)性,，及其是否適用于溫和噬菌體（在腸道中很常見(jiàn)）依然有待觀察,，并且在治療開(kāi)發(fā)上的潛力，例如噬菌體調(diào)節(jié)的免疫力,，依然需要探索,。這一發(fā)現(xiàn)毫無(wú)疑問(wèn)將成為未來(lái)許多關(guān)鍵發(fā)現(xiàn)的跳板。（生物谷Bioon.com）
生物谷推薦英文摘要：
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.
