Bacteriophages encoding human immune evasion factors adapt to livestock-associated MRSA through rounds of integration and excision

In recent years there has been an increase in human infections with methicillin-resistant Staphylococcus aureus (MRSA) originating from livestock and strains carrying bacterial viruses of the Sa3int-family have disseminated into the community. Sa3int phages express immune evasion factors and are common in human staphylococcal strains. As the bacterial attachment site (attB) for Sa3int phages is mutated in livestock-associated strains, the integration frequency is low and a key question is how the phages are established. Here we show that Sa3int phages adapt to alternative bacterial integration sites by mutating the phage attachment sequence, attP, leading to enhanced integration at these sites. Using a model strain carrying the mutated attBLA of livestock-associated strains we find that once established, the Sa3int phage, {Phi}13 is inducible with release of heterogenous phage populations carrying mutations in attP that in part increase homology to alternative integration sites or attBLA. Compared to the original phage, the adaptive mutations increase phage integration in new rounds of infection. Also, Sa3int phages induced from livestock-associated outbreak strains reveal mutated attP sequences. We suspect that promiscuity of the phage-encoded recombinase allows this adaptation and propose it may explain how phages mediate "host jumps" that are regularly observed for staphylococcal lineages.