biostudies-literatureMora-Quilis LEuropean Social Fund PlusGovernment of Valencia Ministry of Innovation Universities Science and SocietyGovernment of Spain Ministry of UniversitiesSpain Ministry of Science Innovation and UniversitiesGeneralitat Valenciana114107https://www.ebi.ac.uk/biostudies/studies/S-EPMC12719783biostudies-literatureUnknown28(12)Capsule loss is a major mechanism by which bacteria evade phage infection. This has traditionally been attributed to mutations in capsule biosynthesis genes. Here, we investigated phage resistance in <i>Klebsiella pneumoniae</i>, a medically relevant encapsulated bacterium. Phage infection rapidly selected for resistant acapsular cells. As expected, transcriptomic analysis revealed a marked downregulation of capsule biosynthesis genes. However, full genome sequencing showed that capsule loss occurred without evidence of mutations, and acapsular phage-resistant cells were able to rapidly restore their capsule once phage pressure was removed. These findings highlight that phage-driven selective pressure can act on non-heritable variation in gene expression, providing a faster and more flexibiScienceReversible phenotypic resistance to phage infection via capsule downregulation in &lt;i&gt;Klebsiella pneumoniae&lt;/i&gt;.PMC12719783RYC2019-028015-IPID2023-150309OB-I00SEJIGENT/2021/014Mora-Quilis LSanjuan RDomingo-Calap PfalseReversible phenotypic resistance to phage infection via capsule downregulation in &lt;i&gt;Klebsiella pneumoniae&lt;/i&gt;.Capsule loss is a major mechanism by which bacteria evade phage infection. This has traditionally been attributed to mutations in capsule biosynthesis genes. Here, we investigated phage resistance in <i>Klebsiella pneumoniae</i>, a medically relevant encapsulated bacterium. Phage infection rapidly selected for resistant acapsular cells. As expected, transcriptomic analysis revealed a marked downregulation of capsule biosynthesis genes. However, full genome sequencing showed that capsule loss occurred without evidence of mutations, and acapsular phage-resistant cells were able to rapidly restore their capsule once phage pressure was removed. These findings highlight that phage-driven selective pressure can act on non-heritable variation in gene expression, providing a faster and more flexib2025-01-01T00:00:00Z2025 Dec2026-06-06T05:24:53.07Z2026-05-26T03:12:17.751ZS-EPMC127197834143807710.1016/j.isci.2025.114107