Abstract
AbstractInfections withPasteurella multocidacan cause significant zoonotic respiratory problems in both humans and animals.In vivotests in mouse infection models were used to investigate the mechanisms of respiratory epithelial barrier dysfunction during respiratory bacterial infection with these pathogens. Results revealed thatP. multocidainfection significantly increased epithelial permeability and increased expression of vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) in murine tracheae and lungs. In murine lung epithelial cell (MLE-12) models,P. multocidainfection decreased the expression of tight junctions (ZO-1) and adherens junctions (β-catenin, E-cadherin), but induced the activation of the hypoxia-inducible factor-1α (HIF-1α) and VEGFA signaling. When expression of HIF-1α is suppressed, the induction of VEGFA and ZO-1expression byP. multocidainfection is decreased. We also found that intervention of HIF-1α and VEGFA signaling affected infection outcomes caused by respiratory bacteria in mouse models. Most importantly, we demonstrated thatP. multocidainfection increased permeability of human respiratory epithelial cells and this process was associated with the activation of the HIF-1α and VEGFA signaling and likely contributes to the pathogenesis ofP. multocidain humans.ImportanceMammalian respiratory epithelium forms the first line of defense against infections withPasteurella multocida, an important zoonotic respiratory pathogen. In this study, we foundP. multocidainfection increased respiratory epithelial permeability and promoted the induction of the hypoxia-HIF-1α-VEGFA axis in both mouse and murine cell models. Similar findings were also demonstrated in human respiratory epithelial cells. The results from this study gain important knowledge about the pathogenesis ofP. multocidacausing infections in both animals and humans.
Publisher
Cold Spring Harbor Laboratory