Friday, May 24, 2013

Our Phage Immune System: Phages Providing Mucosal Immunity

Mucosal surfaces, including those found at the intestines, mouth, nasal passages, and airways, are directly exposed to the external environment and are particularly susceptible to pathogenic bacteria.  Human mucosal surfaces maintain numerous defense mechanisms, both by secreting antimicrobial and immune-stimulating molecules, as well as by maintaining a beneficial commensal microbial community that aids in the prevention of infection [1].  Interestingly, Barr et al recently reported a model (the bacteriophage adherence to mucus [BAM] model) for how phages may also play an important role in mucosal immunity [2].  This is important because it outlines a medically relevant, previously unrecognized tripartite symbiosis between humans (and other metazoans), bacteria, and phages, whereby phages will control bacterial populations to preserve human mucosal health, which is in turn beneficial for both commensal bacteria and phages.  This report also provides us with a new understanding of how phages may interact with their environment, how phages can affect human immunity, and how we might use phages for therapeutic interventions at mucosal surfaces. 

The BAM model proposed by Barr et al (see figure to left) suggests that phages persist longer in mucous environments, compared to other environments, because they have Ig-like domains (immunoglobulin-like domains that bind certain motifs, similar to how antibodies bind to certain motifs) which bind to mucin glycoproteins.  The increased phage persistence results in higher concentrations of phages at the mucus layer, thereby providing a greater chance that phages will infect and destroy a bacterial pathogen that enters the mucus.  The group supports their model by performing a variety of experiments that use T4 bacteriophage, E. coli, and mucus secreting human cells.

Barr et al first used microscopy to show that the phage to bacteria ratio in mucus is, on average, 39:1.  This is almost four times the 10:1 ratio found in most environments.  They then went on to show that phages specifically adhere to the mucin found in mucus.  The group demonstrated, in vitro, that phage containing mucus was better able to protect human cells from death, compared to mucus or phages alone.  They went on to characterize how the phages are able to persist in the mucus, concluding that the Ig-like domains of the highly antigenic outer capsid (hoc) proteins interact with the glycan residues of the mucus glycoproteins.  They also find it worth noting that, while the glycan residues can be variable, the Ig-like domains, which are thought to facilitate the phage-glycan interactions, have also been shown to be highly variable, which may suggest an evolutionary mechanism by which the phage populations can continue to persist optimally in the mucus layer [3].

Although this report will be valuable in our understanding of phage population dynamics, there remain many questions to be addressed. The first aspect of this model that should be addressed, which was mentioned as a future direction by Barr et al in their paper, is the role of temperate phages in the BAM model.  This BAM model is a a proof-of-concept that utilizes lytic T4 phages only.  Gut phage metagenome studies have suggested that temperate phages are prominent members of phage communities, so testing this model with temperate phages will be important [4, 5].  Second, it will be important to show this model holds true in vivo, where conditions are more complex due to the expected diversity of bacteria and phages, as well as the movement and high turnover of mucus.  Finally, the group mentions that the Ig-like domains could be found in phages from a variety of environments, however they were more likely to be found in phages from mucus or mucus-associated environments.  Perhaps diseases associated with aberrant bacterial communities at mucosal surfaces, such as irritable bowel disease, are also associated with less persistent mucosal phages (fewer phages contain the proper Ig-like domain)?

Future work stemming from this research is certainly warranted, and the health implications that come from this will be particularly interesting.  Looking forward, it will be fascinating to see how this research influences work towards understanding phage interactions with their environment, how phages affect human immunity, and how we can better use phages in therapeutic interventions.

Works Cited

1. Bevins CL, Salzman NH. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nature reviews Microbiology. 2011;9(5):356-68. Epub 2011/03/23. doi: 10.1038/nrmicro2546. PubMed PMID: 21423246.

3. Minot S, Grunberg S, Wu GD, Lewis JD, Bushman FD. Hypervariable loci in the human gut virome. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(10):3962-6. Epub 2012/02/23. doi: 10.1073/pnas.1119061109. PubMed PMID: 22355105; PubMed Central PMCID: PMC3309749.

4. Reyes A, Haynes M, Hanson N, Angly FE, Heath AC, Rohwer F, Gordon JI. Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature. 2010;466(7304):334-8. Epub 2010/07/16. doi: 10.1038/nature09199. PubMed PMID: 20631792; PubMed Central PMCID: PMC2919852.

5. Minot S, Sinha R, Chen J, Li H, Keilbaugh SA, Wu GD, Lewis JD, Bushman FD. The human gut virome: inter-individual variation and dynamic response to diet. Genome research. 2011;21(10):1616-25. Epub 2011/09/02. doi: 10.1101/gr.122705.111. PubMed PMID: 21880779; PubMed Central PMCID: PMC3202279.


  1. You made me want to read the article, I just read the news headlines and now I want to read the article, thanks!

  2. I'm glad to hear it! It is a really cool article, definitely worth a read.

  3. Bateria associated with mucosal surfaces can also be exploited for the generation of novel vaccines that are more efficacious, safer and less expensive to produce than current vaccines. Furthermore, this embodiment can be used to deliver regulators of bacterial metabolism and gene expression to modulate critical interactions between the microbiome and the human host that are linked to disease states or microbial pathogenicity in humans.

  4. Before reading this article, I have no idea for phage, which is so important to our immune system. I want to know more about the process, such as the immune response of phage.