Virulence attenuation in ST11-K64 <i>Klebsiella pneumoniae</i> explains its divergent clinical manifestation from ST23-K1

The clinical threat posed by Klebsiella pneumoniae is dual-faceted, encompassing both hypervirulence and carbapenem resistance. The emergence of hypervirulent carbapenem-resistant K. pneumoniae (hv-CRKP) merges these threats, with the ST11-K64 clone being a dominant and concerning lineage. However, its clinical presentation diverges from the classic hypervirulent Klebsiella pneumoniae (hvKp); hv-CRKP is isolated from respiratory sites but is notably absent from pyogenic liver abscesses. This distinct clinical niche prompted us to investigate the underlying pathogenicity differences. Among 847 clinical Klebsiella pneumoniae isolates, 157 (18.5%) were identified as hv-CRKP. From this hv-CRKP collection, we selected five representative ST11-K64 isolates for downstream phenotypic and mechanistic analyses. Despite its prevalence and multidrug resistance, the ST11-K64 clone exhibited significantly attenuated lethality in mouse models compared to ST23-K1. Crucially, in a murine intestinal colonization model that mimics natural infection, only ST23-K1 successfully colonized the gut, caused bacteremia, and formed liver abscesses. In contrast, ST11-K64 strains showed impaired intestinal colonization and failed to translocate to the liver. Phenotypic profiling showed reduced capsule viscosity and siderophore production in ST11-K64 relative to ST23-K1, accompanied by diminished macrophage and Kupffer cell-associated fitness. RT-qPCR identified higher expression of rmpA, rmpA2, iroB, and iucA in ST23-K1, and isogenic deletion and complementation of rmpA2 or iucA in the ST23-K1 background supported their contribution to capsule/siderophore-associated phenotypes and intracellular survival in RAW264.7 macrophages. Together, these results indicate that while ST11-K64 hv-CRKP represents a serious antimicrobial-resistance threat, its invasive pathogenicity is route- and context-dependent and does not fully recapitulate the classic entero-hepatic hypervirulence of ST23-K1.