Host-encoded DNA methyltransferases modify the epigenome and host tropism of invading phages
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A part of prokaryotic DNA methyltransferases (MTases) is associated with phage-defense systems (e.g., restriction-modification [RM] system) to combat the invasion of foreign DNA (e.g., phages). To date, the epigenomes of host and phage during the infection cycle have not been directly observed, and their association with phage infection efficiency remains unclear. Here, using the wide-host-range phage KHP30T and three Helicobacter pylori strains (26695, 3401T, and HPK5) that possess different sets of MTases, we investigated changes in infection efficiency and epigenomes of the phage via adaptation to each host strain. Based on the designed multi-stage infection flow, adapted phages showed higher titers only against the last infected H. pylori strain, suggesting an attendant change in host tropism. Using single-molecule real-time sequencing, we retrieved each complete genome and 15 and 20 methylated motifs from H. pylori 3401T and HPK5, respectively. In general, the methylated motifs were common between pairs of adapted phages and the last infected host strain. Some exceptions were identified that may arise from phase variation. Our results demonstrate phage genomes are methylated by host-encoded MTases during the infection cycle as they pass through the host RM system, resulting in increased infection efficiency of phages against the same host strain.