Host-encoded DNA methyltransferases modify the epigenome and host tropism of invading phages. Helicobacter pylori

A part of prokaryotic DNA methyltransferase (MTase) is associated with phage-defense systems (e.g., restriction-modification [RM] system) to combat the invasion of foreign DNA, such as phages. However, the epigenomes of host and phage during infection cycle have not been directly observed, and their association with infection efficiency of phage remains unclear. Here, using the wide-host-range phage KHP30T and three Helicobacter pylori strains (26695, 3401T, and HPK5) that possess different MTase sets, we investigated the 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 a posterior 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. The methylated motifs were overall shared between pairs of adapted phages and the last infected host strain, although some exceptions might be explained by phase variation. Our results demonstrated phages acquire methylation modification on their genome by host-encoded MTases during infection cycle and pass through the host RM systems, resulting in increased infection efficiency against the same host strain.