The genetic basis of phage susceptibility, cross-resistance and host-range in Salmonella
Benjamin A. Adler, Alexey E. Kazakov, Crystal Zhong, Hualan Liu, Elizabeth Kutter, Lauren Michelle Lui, Torben Nielsen, Héloïse Carion, Adam M. Deutschbauer, Vivek K. Mutalik, Adam P. Arkin
Abstract
Though bacteriophages (phages) are known to play a crucial role in bacterial fitness and virulence, our knowledge about the genetic basis of their interaction, cross-resistance and host-range is sparse. Here, we employed genome-wide screens in Salmonella enterica serovar Typhimurium to discover host determinants involved in resistance to eleven diverse lytic phages including four new phages isolated from a therapeutic phage cocktail. We uncovered 301 diverse host factors essential in phage infection, many of which are shared between multiple phages demonstrating potential cross-resistance mechanisms. We validate many of these novel findings and uncover the intricate interplay between RpoS, the virulence-associated general stress response sigma factor and RpoN, the nitrogen starvation sigma factor in phage cross-resistance. Finally, the infectivity pattern of eleven phages across a panel of 23 genome sequenced Salmonella strains indicates that additional constraints and interactions beyond the host factors uncovered here define the phage host range.