Plug-and-play evolution of the Klebsiella pneumoniae capsule locus enables serotype exchange across genetic backgrounds.

Understanding how complex, multi-gene systems evolve and function across genetic backgrounds is a central question in molecular evolution. While such systems often impose costs through epistatic interactions, some may behave as modular, "plug-and-play" units that retain function with minimal disruption. Here, we tested this using the polysaccharide capsule locus of Klebsiella pneumoniae, a highly exchangeable and fast-evolving locus, as a model. We genetically engineered capsule exchanges (swaps) across diverse genetic backgrounds and combined transcriptomics, fitness assays, and evolution experiments to show that capsule exchange has negligible effects on global expression and only marginal fitness costs, regardless of capsule type (or K type). Adaptation to capsule-costly environments consistently reduced capsule production regardless of K type, revealing shared adaptive trajectories rather than K type-specific pathways. Moreover, K type-specific traits involved in bacterial virulence, such as biofilm formation and hypermucoviscosity, were conserved across genetic backgrounds. This reveals that capsule swapping can directly shape host-pathogen interactions and influence within-patient evolution. Our findings provide strong evidence that capsule loci display plug-and-play dynamics: they are transferable, functional across contexts, and minimally disruptive to the host genome. This allows capsules to be seamlessly swapped, and help explain the evolutionary success, ecological versatility, and pervasive exchangeability of capsules in K. pneumoniae.