Methylation warfare: interaction of pneumococcal bacteriophages with their host.

Virus-host interactions are regulated by complex co-evolutionary dynamics. In S. pneumoniae phase-variable Type I restriction modification (R-M) systems are part of the core genome. We hypothesised that the ability of the R-M systems to switch between six target DNA specificities also has a key role in preventing the spread of bacteriophages. Using the streptococcal temperate bacteriophage SpSL1, we showed that the variants of both the SpnIII and SpnIV R-M system were able to restrict invading bacteriophage proportional to the number of target sites in the bacteriophage genome. In addition to restriction of lytic replication SpnIII also led to abortive infection in the majority of host cells. During lytic infection, transcriptional analysis found evidence of phage-host interaction through the strong upregulation of the nrdR nucleotide biosynthesis regulon. During lysogeny, the phage had less effect on host gene regulation. This research demonstrates a novel combined bacteriophage restriction and abortive infection mechanism, highlighting the importance that the phase-variable Type I R-M systems have in the multi-functional defence against bacteriophage infection in the respiratory pathogen S. pneumoniae.Importance With antimicrobial drug resistance becoming an increasing burden on human health, much attention has been focussed on the potential use of bacteriophages and their enzymes as therapeutics. However, the investigations into the physiology of the complex interactions of bacteriophages with their hosts has attracted far less attention in comparison. This work describes the molecular characterisation of the infectious cycle of a bacteriophage of the important human pathogen Streptococcus pneumoniae and explores the intricate relationship between phase variable host defence mechanisms and the virus. This is the first report showing how a phase variable type I restriction modification system is involved in bacteriophage restriction, whilst also providing an additional level of infection control through abortive infection.