# Evolutionary Origins and Virulence Determinants of ST25 Hypervirulent Klebsiella pneumoniae in Swine: Genomic Insights and Functional Validation

## TL;DR

This study investigates a highly virulent strain of Klebsiella pneumoniae from swine, revealing its close relation to human strains and identifying a key virulence factor and a potential phage therapy.

## Contribution

The study identifies wcaJ/wzc-mediated capsule synthesis as a critical virulence determinant and proposes phage therapy as a treatment for hypervirulent K. pneumoniae.

## Key findings

- The swine-derived HvKp strain KPB (ST25) clusters closely with clinical isolates, indicating zoonotic transmission risks.
- Capsule-deficient HvKp mutants showed 100% reduced lethality in mouse models, highlighting capsule synthesis as a key virulence factor.
- Phage therapy achieved 100% survival in infected mice at low doses, suggesting a promising treatment strategy.

## Abstract

The global spread of multidrug‐resistant hypervirulent Klebsiella pneumoniae (MDR‐HvKp), among which carbapenem‐resistant strains are of major concern, poses a severe threat to public health due to its high mortality rate and extremely limited treatment options. While human‐derived HvKp strains are well‐studied, animal‐origin variants remain poorly characterized. Here, we isolated a HvKp strain KPB from a swine farm in China, exhibiting high mortality and extreme virulence (LD50 = 20 CFU). Phylogenomic analysis of 342 K. pneumoniae genomes revealed that the swine‐derived KPB (sequence type 25 [ST25] lineage) clusters closely with clinical isolates, suggesting zoonotic transmission risks. Targeted mutagenesis identified wcaJ/wzc‐mediated capsule synthesis as the critical virulence determinant, with capsule‐deficient mutants showing 100% reduced lethality in mouse infection models. Building on this, we developed a phage therapy achieving 100% survival in infected mice at 101 PFU doses. These findings highlight the evolutionary convergence of animal and human HvKp strains and propose phage‐based strategies as a promising countermeasure against infections due to HvKp. Our study underscores the urgency of One Health surveillance to mitigate zoonotic threats.