Description du projet
Coopération entre le bactériophage et son hôte bactérien pendant l’infection
Les bactériophages (Bp) sont des parasites qui utilisent les cellules bactériennes pour se propager et qui jouent un rôle dans l’évolution bactérienne. Les Bp lytiques entrent dans un cycle de production après l’infection, générant et libérant des virions par lyse cellulaire; les Bp lysogènes se propagent sans activer le cycle lytique. Leur génome s’intègre au chromosome bactérien en tant que prophage et se reproduit avec le chromosome hôte, mais ils peuvent déclencher une production lytique dans des conditions de stress. Une étude récente a démontré que le prophage infectieux renforce la virulence de Listeria monocytogenes, l’hôte bactérien, par le biais d’un comportement adaptatif et dépend de facteurs de régulation dérivés des restes de prophages présents dans le génome de la bactérie. Le projet CoPathoPhage, financé par l’UE, étudiera les mécanismes de régulation croisée et de coopération des éléments phagiques, ce qui générera de nouvelles connaissances sur la coexistence entre les bactéries et les phages.
Objectif
Most bacterial pathogens are lysogens, namely carry DNA of active 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 will study the hypothesis that a complex bacteria-phage cooperative adaptation supports virulence during mammalian infection while preventing inadvertent killing by phages. Several years ago, we uncovered a novel pathogen-phage interaction, in which an infective prophage 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- completely dependent on regulatory factors derived from inactive prophage remnants that reside in the Lm chromosome. These findings lead us to propose that the intimate cross-regulatory interactions between all phage elements within the genome (infective and remnant), are crucial in promoting bacteria-phage patho-adaptive behaviours in the mammalian niche and thereby bacterial virulence. In the proposed project, we will investigate specific cross-regulatory and cooperative mechanisms of all the phage elements, study the domestication of phage remnant-derived regulatory factors, and examine the hypothesis that they collectively form an auxiliary phage-control system that tempers infective phages. Finally, we will examine the premise that the mammalian niche drives the evolution of temperate phages into patho-adaptive phages, and that phages that lack this adaptation may kill host pathogens during 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.
Champ scientifique
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
69978 Tel Aviv
Israël