Bacteriophages: an underestimated role in human and animal health?

Abstract

Metagenomic approaches applied to viruses have highlighted their prevalence in almost all microbial ecosystems investigated. In all ecosystems, notably those associated with humans or animals, the viral fraction is dominated by bacteriophages. Whether they contribute to dysbiosis, i.e., the departure from microbiota composition in symbiosis at equilibrium and entry into a state favoring human or animal disease is unknown at present. This review summarizes what has been learnt on phages associated with human and animal microbiota, and focuses on examples illustrating the several ways by which phages may contribute to a shift to pathogenesis, either by modifying population equilibrium, by horizontal transfer, or by modulating immunity.

Keywords: biological weapon; community shuffling; digestive tract; horizontal transfer; virome.

Figure 1

(A) The lytic and lysogenic life cycles of phages (scheme taken from Dr Gary Kaiser, with permission). Virulent phages perform only lytic cycles (steps 1 to 5), they adsorb to the bacterial surface (1), inject their DNA (2), replicate it (3), produce capsid proteins that assemble together (4), and finally lyse their host (5). Temperate phages can proceed similarly or shift to a lysogenic cycle (6), where they enter a silent stage of prophage (usually integrated into the bacterial genome), and are replicated passively by the bacterial machinery (7). Either a rare stochastic event or a stress induces the prophage (8), which then comes back into a lytic cycle. (B). The various states of a poly-lysogen strain. Most bacterial strains are poly-lysogens, they host more than one prophage. As a consequence, a population may differentiate into various states: it can produce (1) background levels of virions, (2) excise some prophage and reveal a new phenotype by restoration of the gene interrupted by the prophage [producing for instance a surface protein, yellow square (Rabinovich et al., 2012)], (3) adsorb virions and use them as virulence factors (Mitchell et al., 2007).

Figure 2

Phage richness in various viromes. Scores estimated with PHACCS in five environments are shown (blue, open environments, orange, human samples). PHACCS is a program estimating species richness from contig spectra (Angly et al., 2005). Ocean: mix of four oceans samples (Angly et al., 2006). Hot springs: Yellowstone (Schoenfeld et al., 2008), saliva: average of 5 subjects (Pride et al., 2012), lung: non-cystic fibrosis samples (Willner et al., 2009), feces: median value of 12 samples (Reyes et al., 2010).

Figure 3

(A) In the Kill the winner scheme, viruses are more abundant than bacteria, but do not infect them because of their low concentration (step 1). However, if some bacteria overgrow (step 2), and reach the threshold above which phages can absorb and predate them, they will lyse, and the system will shift back to its initial state (3). (B) In the Kill the relative scheme, phages do not need to be abundant, they are produced by lysogen strains (step 1) and kill their relatives that are not resistant to the phage (bacteria of the same color, but lighter, with a “-”label). The net result is an advantage of lysogenic populations relative to non-lysogens (step 2). (C) In the Community shuffling scenario, temperate phages act negatively on their host by killing them upon sensing a mild stress that would not have killed a non-lysogen (step 2). A positive feed-back loop may even take place if the massive lysis leads to an host reaction, such as inflammation (orange arrow). The net result is a global displacement of population, and possibly dysbiosis. (D) Temperate phages can act profoundly on bacterial population without lysing them: in the Invade the relative scheme, the prophage propagates itself by infecting new hosts without lysing them, but by establishing lysogeny (step 2, the + sign indicates new lysogens).