Wzi modulates immune evasion of hypervirulent Klebsiella pneumoniae in a CPS-dependent and independent manner.

Hypervirulent Klebsiella pneumoniae (hvKP) poses a significant public health threat due to its ability to cause severe invasive infections with higher mortality than classical strains. Understanding its pathogenesis is essential for devising effective treatment strategies. We analyze shared virulence-associated genes from three hvKP transposon mutagenesis libraries and identify wzi as a key virulence determinant of hvKP. We demonstrate that Wzi deficiency reduces CPS production in K. pneumoniae, differing from its function as a CPS anchor in Escherichia coli. Importantly, Wzi exerts a pivotal role in K. pneumoniae pathogenicity in vitro and in vivo through CPS-dependent and -independent mechanisms. It promotes hvKP survival in the host by suppressing IFN-γ-related cytokine secretion during early infection via CPS-dependent pathways. Wzi and CPS independently trigger sustained neutrophil recruitment through CXCL1 upregulation, resulting in pulmonary barrier damage and enhanced bacterial systemic dissemination for encapsulated K. pneumoniae. Wzi further enables K. pneumoniae to evade neutrophil-mediated clearance in a CPS-dependent manner. Notably, wzi sequence polymorphisms significantly influenced serum resistance independent of CPS, with hvKP-associated alleles conferring the highest resistance. Our findings collectively highlight Wzi as a CPS-dependent and -independent virulence factor that mediates immune evasion and tissue invasion of hvKP, highlighting its potential as a therapeutic target for combatting hvKP infections.