The Mechanobiology of Klebsiella pneumoniae infections

Klebsiella pneumoniae (Kp) is an opportunistic pathogen and one of the leading antibiotic-resistant threats globally, yet many aspects of its pathogenicity remain poorly understood. Unlike classical pathogens, Kp does not rely on potent cytotoxins but instead exploits physical traits such its capsule to colonize host tissues and evade immune clearance. Kp infections often manifest through striking mechanical behaviors, yet its physiology has been almost exclusively studied from a biochemical perspective. Colonies are frequently described in qualitative mechanical terms, with hypervirulent strains labeled "hypermucoviscous" due to their extreme mucoid phenotype. The function of such mechanical phenotypes during infection has yet to be investigated mechanistically. In MUCOID, we will reveal how mechanics at mucosal surfaces regulate Kp pathogenicity. We propose to integrate quantitative biophysical approaches with tissue-engineered human lung and colon organoids models to investigate how mechanical cues shape infection dynamics. First, we will dissect how capsule mechanochemical properties determine the viscoelastic behavior of Kp multicellular structures including biofilms, and how they affect their spatial organization and resilience under flow. Second, we will reveal how expanding Kp multicellular assemblies disrupt epithelial integrity and enable translocation across lung and gut organoids, and how the capsule contributes to this mechanical mode of infection. Third, we will identify how Kp senses mechanical stimuli such as surface contact and confinement, and map the regulatory pathways driving mechano-responsive gene expression. Together, this multidisciplinary effort will establish a new framework for understanding infection biology through the lens of mechanics and generate broadly applicable tools and models to study mucosal pathogens in realistic biophysical contexts.