Capsular Polysaccharides, Type VI Secretion System, and Vascular Homeostasis in Klebsiella pneumoniae Pathogenesis

Abstract

Klebsiella pneumoniae is an important opportunistic pathogen responsible for severe hospital- and community-acquired infections, with multidrug-resistant and hypervirulent strains posing an increasing therapeutic challenge. Capsular polysaccharides (CPS) and the Type VI secretion system (T6SS) are well-established virulence determinants involved in immune evasion, bacterial competition, colonization, and dissemination. Increasing experimental evidence also points to effects on vascular biology. In particular, CPS has been linked to impaired endothelial nitric oxide synthase (eNOS) signaling, while selected T6SS effectors can promote mitochondrial oxidative stress and endothelial dysfunction. These mechanisms may contribute to impaired vasodilation, vascular permeability, inflammation, thrombosis, and tissue hypoperfusion during severe infection. This narrative review examines how CPS and T6SS interact with host pathways that regulate endothelial function, including nitric oxide signaling, reactive oxygen species, inflammatory pathways, and endothelial barrier integrity. It also considers the contributions of other virulence determinants, including lipopolysaccharide, siderophores, fimbriae, and biofilm formation. Importantly, the available evidence is weighted according to its source: much of the mechanistic evidence comes from cell and animal models, whereas direct clinical validation of CPS/T6SS-mediated vascular signaling remains limited. Therapeutic strategies are therefore discussed according to their current developmental stage, distinguishing established antimicrobial treatment from experimental pathogen-directed and host-directed approaches. Anti-capsular therapies, T6SS inhibition, bacteriophage-based approaches, immunomodulation, endothelial protection, and targeted drug delivery may complement antimicrobial therapy in the future, but most remain preclinical. A clearer understanding of the temporal relationship between bacterial virulence, endothelial injury, inflammation, coagulation, and organ dysfunction will be essential for translating these findings into clinically useful interventions.