The Impact of Siderophores and Iron Acquisition on Klebsiella Pneumoniae Pathogenesis.

[摘要] Klebsiella pneumoniae is a Gram-negative bacterium that can cause a wide range of infections, including pneumonia, urinary tract infection, wound infection, and sepsis. K. pneumoniae is the most common species of carbapenem-resistant Enterobacteriaceae, of which isolates are resistant to all or nearly all antibiotics. To acquire iron required for replication, K. pneumoniae secretes siderophores, small molecules with high affinity for iron. In addition, recent research has identified novel, non-iron acquisition functions for siderophores. This thesis describes the inflammatory properties of siderophores and how siderophore secretion by K. pneumoniae impacts bacterial infection. In vitro, respiratory epithelial cells treated with siderophores and the host protein Lcn2 induced secretion of pro-inflammatory cytokines including IL-8, IL-6, and CCL20. Additionally, siderophores stabilized the master transcription factor HIF-1α. In vivo studies identified a role for siderophores in the induction of the host immune response, including IL-6, KC, and MIP-2 secretion, during pneumonia. Siderophores were also shown to promote bacterial dissemination to the spleen, which required HIF-1α from alveolar epithelial cells. Finally, clinical isolates of K. pneumoniae can be divided into two clades based on their genomic contents, including a deletion of the siderophore exporter, entS. Transcriptional analysis (RNASeq) under iron-limited growth conditions identified novel iron acquisition mechanisms potentially utilized by the isolates that contain the deletion in entS. Combined, these results demonstrate novel roles for siderophores in the induction of inflammation and bacterial dissemination during infection, and identify novel potential iron acquisition pathways that may be active in carbapenem-resistant K. pneumoniae. Iron acquisition in non-siderophore dependent manners may allow bacteria to acquire iron in a manner that does not perturb the host immune response. By understanding the host response to siderophores, novel therapies can be designed to combat infection with siderophore-secreting bacteria.

[发布机构] University of Michigan

[效力级别] siderophores

[关键词] Klebsiella pneumoniae;siderophores;iron acquisition;pneumonia;Microbiology and Immunology;Science;Microbiology and Immunology