Reversible phenotypic resistance to phage infection via capsule downregulation in Klebsiella pneumoniae

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 flexible resistance mechanism compared to the traditional mutation-selection process. This reversible resistance may complicate predictability and limit the long-term efficacy of phage therapy.