Most bacterial pathogens are lysogens, namely carry DNA of phages within their genome, referred to as prophages. While these prophages have the potential to turn under stress into infective viruses which kill their host bacterium in a matter of minutes, it is unclear how pathogens manage to survive this internal threat under the stresses imposed by their invasion into mammalian cells. In the proposed project, we aim to study the hypothesis that phages cooperate with the bacterial hosts in the mammalian environment, and thus support their virulence. Several years ago, we uncovered a novel pathogen-phage interaction, in which an infective phage promotes the virulence of its host, the bacterial pathogen Listeria monocytogenes (Lm), via adaptive behaviour. More recently, we discovered that the prophage, though fully infective, is non-autonomous, and is completely dependent on another phage element (cryptic) that inhabit the Lm chromosome. These findings lead us to propose that the intimate cross-regulatory interactions between all phage elements within the bacterial chromosome (infective and cryptic), are crucial in promoting bacteria-phage patho-adaptive behaviours in the mammalian niche and thereby bacterial virulence. In this project, we investigate specific cross-regulatory and cooperative interactions between the phage elements, study the domestication of phage derived regulatory factors, and examine the hypothesis that they collectively form an auxiliary regulatory system that tempers infective phages. Finally, we examine the idea that the mammalian niche drives the evolution of temperate phages into patho-adaptive phages, and phages that lack this adaptation kill their hosts during mammalian infection. This work is expected to provide novel insights into bacteria-phage coexistence in mammalian environments and to facilitate the development of innovative phage therapy strategies.
