Multiple effects of the bacterial DNA-binding protein SarA on the life cycle of Staphylococcus aureus phages

Staphylococcus aureus is a major opportunistic pathogen in humans and animals. More than 90% of human nasal S. aureus isolates carry Sa3int-phages that integrate into the bacterial hlb gene coding for a sphingomyelinase. Sa3int-phages encode highly human-specific virulence factors that enable S. aureus to adapt to the human host. Thus, balancing mechanisms are necessary for the phage-bacteria coexistence. However, the factors that coordinate these interactions have yet to be discovered. Here, we elucidate the impact of the DNA-binding protein SarA on the life cycle of two prototypic S. aureus phages, Sa3int Φ13 and Sa5int Φ11. SarA promotes the propagation of both phages, albeit via different mechanisms. SarA promotes Φ11 propagation by repressing the glycosyltransferase TarM, which affects the glycosylation pattern of the phage receptor, wall teichoic acid, thereby improving phage adsorption. SarA also dampens the DNA damage response as indicated by the downregulation of the ci and mor phage promoters and the umuC SOS target gene, as well as inhibition of Φ11 inducibility. For Φ13, however, SarA promotes phage replication rather than inhibiting phage induction. The replication-deficient phage Φ13K-rep was SarA-insensitive, and phage gene expression was unaltered in the sarA mutant. These results highlight SarA as a regulator of temperate phage propagation and support its role as a DNA structural protein that promotes phage replication. IMPORTANCE: The dynamic gain and loss of temperate phages is crucial for bacteria to adapt to specific niches. In Staphylococcus aureus Sa3int, phages are highly prevalent in human strains but are missing in most animal strains. The mechanisms that balance phage-bacteria coexistence are only partially understood. We demonstrate that the DNA-binding protein SarA is a key regulator of the phage life cycle. SarA protects bacteria from phage induction in response to DNA damage, yet it can also promote phage propagation by altering the phage receptor or interfering with phage replication. SarA likely functions not only as a transcriptional factor, but also as a bacterial chromosome structural component that controls the phage life cycle at different levels.