Descrizione del progetto
Cooperazione tra batteriofago e ospite batterico durante l’infezione
I batteriofagi sono parassiti che utilizzano le cellule batteriche per diffondersi e svolgono un ruolo nell’evoluzione batterica. I batteriofagi litici entrano in un ciclo produttivo dopo l’infezione, generando e rilasciando virioni tramite lisi, mentre i batteriofagi lisogenici si diffondono senza attivare il ciclo litico. Il loro genoma si integra nel cromosoma batterico come profago e si replica con il cromosoma ospite, ma può passare alla produzione litica in condizioni di stress. Uno studio recente ha dimostrato che il profago infettivo favorisce la virulenza dell’ospite batterico Listeria monocytogenes attraverso un comportamento adattivo e dipende da fattori regolatori derivati dai residui del profago nel genoma batterico. Il progetto CoPathoPhage, finanziato dall’UE, analizzerà i meccanismi di regolazione incrociata e cooperativa degli elementi fagici, fornendo nuove informazioni sulla coesistenza tra batteri e fagi.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
69978 Tel Aviv
Israele