Modelling the gastrointestinal carriage of Klebsiella pneumoniae infections.

Abstract

Klebsiella pneumoniae is a leading cause of nosocomial and community acquired infections, making K. pneumoniae the second pathogen associated with the most deaths attributed to any antibiotic resistant infection. K. pneumoniae colonises the nasopharynx and the gastrointestinal tract in an asymptomatic manner without dissemination to other tissues; importantly gastrointestinal colonisation is a requisite for infection. Our understanding of K. pneumoniae colonisation is still based on interrogating mouse models in which animals are pre-treated with antibiotics to disturb the colonisation resistance imposed by the gut microbiome. In these models, infection disseminates to other tissues. Here, we report a murine model to allow for the study of the gastrointestinal colonisation of K. pneumoniae without tissue dissemination. Hypervirulent and antibiotic resistant strains stably colonise the gastrointestinal tract of in an inbred mouse population without antibiotic treatment. The small intestine is the primary site of colonisation followed by a transition to the colon over time without dissemination to other tissues. Our model also mimics the disease dynamics of metastatic K. pneumoniae strains able to disseminate from the gastrointestinal tract to other sterile sites. Colonisation is associated with mild to moderate histopathology, no significant inflammation, and no effect on the richness of the microbiome. Our model recapitulates the clinical scenario in which antibiotic treatment disturbs the colonisation of K. pneumoniae resulting in dissemination to other tissues. Finally, we establish that the capsule polysaccharide is necessary for the colonisation of the large intestine whereas the type VI secretion system contributes to colonisation across the gastrointestinal tract. IMPORTANCEKlebsiella pneumoniae is one of the pathogens sweeping the World in the antibiotic resistance pandemic. Klebsiella colonises the nasopharynx and the gut of healthy subjects in an asymptomatic manner, being gut colonisation a requisite for infection. This makes essential to understand the gastrointestinal carriage to prevent Klebsiella infections. Current research models rely on the perturbation of the gut microbiome by antibiotics, resulting in an invasive infection. Here, we report a new model of K. pneumoniae gut colonisation that recapitulates key features of the asymptomatic human gastrointestinal tract colonisation. In our model, there is no need to disturb the microbiota to achieve stable colonization without dissemination to other tissues. Our model recapitulates the clinical scenario in which antibiotic treatment triggers invasive infection. We envision our model will be an excellent platform to test therapeutics to eliminate Klebsiella asymptomatic colonisation, and to investigate factors enhancing colonisation and invasive infections.