Date Published: October 25, 2018
Publisher: Public Library of Science
Author(s): Breck A. Duerkop, Richard C. Condit.
Phages are ubiquitous to body surfaces, including the skin, oral cavity, lungs, intestine, and urinary tract [1, 5–10]. The majority have double stranded DNA (dsDNA) genomes and belong to the Caudovirales order of tailed phages [1, 8, 9]. Metagenomic analyses have identified both single stranded DNA (ssDNA) and RNA phages as components of the microbiota . Considering that dsDNA and ssDNA phage metagenomes are more frequently studied, the abundance and diversity of RNA phages are underrepresented and reflect a key knowledge gap of the mammalian microbiota.
The mucosal surfaces of animals are covered with mucin glycoproteins, and phages associate with these surfaces and bind to mucin [7, 19, 20]. Through a mechanism of bacteriophage adherence to mucin (BAM), phages with immunoglobulin (Ig)-like domains in their capsids are capable of binding to host mucins through interactions with glycan moieties  (Fig 1A). Ig-like domains are common among phages within the microbiota, and it is hypothesized that BAM provides phage-mediated antibacterial protection of animal mucosal surfaces [19, 21].
The phage component of the intestinal microbiota is an untapped source for further understanding the complexity of host–microbiota interactions during health and disease. Elevated levels of dsDNA phages are associated with inflammatory bowel disease (IBD), and it appears that abundance and diversification of intestinal phages during IBD are independent of changes in the host bacterial community [24, 25]. This suggests that the intestinal immune response during IBD may be a contributing factor to the assembly of phage communities in vivo. Indeed, it has been shown that host inflammation has a strong influence on phage composition in the intestine  (Fig 1C). Additionally, alterations in intestinal phage composition precede the development of type 1 diabetes in children . In this study, specific phages were shown to correlate with the onset of disease and suggest that there may be a phage component to the development of autoimmunity. The correlation of aberrant phage community composition to disease status suggests that phages could be utilized as biomarkers for the early detection of diseases in which environmental microbial factors are at play.
Renewed interest in phage therapy for the treatment of infectious bacterial diseases has led to paradigm–shifting observations of how phages influence the function of the immune system. A seminal discovery showed that phages collaborate with neutrophils to promote efficient bacterial clearance during lung infection . This process was dependent on functional Toll-like receptor signaling, emphasizing the importance of the immune system in phage-mediated antibacterial activity. Because the lung is an environment rich in natural phage diversity , it stands to reason that phages may dictate the health of this environment through interactions with the immune system.
The study of phage communities within the microbiota and other host-associated polymicrobial environments represents an emerging field, and there are not yet clear criteria for how these resident viruses impact health and disease. Phages are known to influence the metabolic functions of their bacterial hosts and, in this capacity, may indirectly influence mammalian biological processes by altering the physiological state of bacteria. It has been determined that phages strongly influence bacterial community structure and could be harnessed to direct the assembly of bacterial communities to promote microbial homeostasis. Finally, phages are being reconsidered as therapeutic agents to target and kill bacterial pathogens or dysregulated members of the microbiota. The administration of lytic phages or the controlled induction of prophages from bacterial chromosomes may provide new strategies to diversify or restrict microbial communities, likely drawing significant interest towards translational medical applications. The discovery that specific phages are associated with certain diseases suggests that, in addition to therapeutics, phages may serve as relevant biomarkers of disease. The study of phage biology within the context of the mammalian microbiota provides new opportunities to study phage interactions with both bacteria and animals. The future of phage research in biomedicine has great promise and is ripe for new discoveries.