RpoE-mediated virulence attenuation elicits protective immunity in hypervirulent Klebsiella pneumoniae

The global emergence of hypervirulent Klebsiella pneumoniae (hvKP) and extensively drug-resistant (XDR) phenotypes has precipitated a severe public health crisis with limited therapeutic options. In particular, the hypervirulent ST65 and ST23 lineages, alongside the carbapenem-resistant ST11 lineage, have been reported to be emerging globally with the potential for continued large-scale dissemination. Despite the urgent need for preventive strategies, the regulatory networks governing hvKP virulence and their potential as targets for live attenuated vaccines remain inadequately explored. In this study, we elucidate a pathogenic mechanism driven by the transcription factor RpoE. Deletion of the rpoE gene in hvKP significantly attenuated virulence by directly downregulating the expression of type 3 fimbriae (T3F) and subsequently impairing biofilm formation. Based on this marked virulence attenuation, we evaluated the ΔrpoE strain as a potential live attenuated vaccine candidate. Remarkably, immunization elicited protective immune responses involving functional antibody responses and CD4⁺ T cell-associated immunity, conferring host protection against the tested ST11, ST23, and ST65 clinical isolates. Our findings define an RpoE-T3F regulatory axis involved in hvKP virulence and support ΔrpoE as a potential live attenuated vaccine candidate with protective efficacy against these tested clinically relevant KP strains.