Close Encounters of Three Kinds: Bacteriophages, Commensal Bacteria, and Host Immunity

Abstract

Recent years have witnessed an explosion of interest in the human microbiota. Although commensal bacteria have dominated research efforts to date, mounting evidence suggests that endogenous viral populations (the 'virome') play key roles in basic human physiology. The most numerous constituents of the human virome are not eukaryotic viruses but rather bacteriophages, viruses that infect bacteria. Here, we review phages' interactions with their immediate (prokaryotic) and extended (eukaryotic) hosts and with each other, with a particular emphasis on the temperate phages and prophages which dominate the human virome. We also discuss key outstanding questions in this emerging field and emphasize the urgent need for functional studies in animal models to complement previous in vitro work and current computational approaches.

Keywords: bacteriophage; lysogeny; microbiota; phageome; prophage; virome.

Figure 1.. Lytic and Lysogenic Cycles of Phage Replication.

The lytic cycle (top) is characterized by the immediate transcription, replication, and translation of the newly injected phage genome, assembly of mature phage particles, and lysis of the bacterial cell. In the lysogenic cycle (bottom), the phage genome is not immediately replicated but instead integrated into the bacterial chromosome (or maintained episomally) as a prophage. Most phage genes – but not all – are transcriptionally repressed in prophages, which are replicated by bacterial machinery and segregated to daughter cells upon binary fission. DNA damage and other stimuli, along with stochastic fluctuations in gene expression, can result in prophage induction, in which the prophage genome is derepressed, excised, and replicated lytically.

Figure 2.

In this model, prophages block superinfection by other phages, and phage infection contributes to horizontal gene transfer via transduction and transformation. Phage particles adhere to epithelial mucus, where they reduce the densities of potentially invasive bacteria, and are occasionally translocated across the epithelium from the intestinal lumen. Phage antigens and bacterial debris released by lysis are transported through microfold (M) cells in Peyer’s patches and sampled by dendritic cells, which also acquire antigens directly from the intestinal lumen via cellular extensions between epithelial cells. These bacterial and phage antigens are presented to B and T cells in the Peyer’s patches and mesenteric lymph nodes, thereby driving a variety of immune responses not shown. Importantly, aspects of this model have yet to be explicitly demonstrated (see text).