Klebsiella pneumoniae Siderophores Induce Inflammation, Bacterial Dissemination, and HIF-1α Stabilization during Pneumonia
Authors: Holden Victoria I. , Breen Paul , Houle Sébastien , Dozois Charles M. , Bachman Michael A. 
Published: September 2016

Klebsiella pneumoniaeis a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance.K. pneumoniaerequires secretion of siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of siderophores secreted byK. pneumoniaeduring infection can impact tissue localization, systemic dissemination, and host survival. However, the effect of these potent iron chelators on the host during infection is unknown.In vitro, siderophores deplete epithelial cell iron, induce cytokine secretion, and activate the master transcription factor hypoxia inducible factor-1α (HIF-1α) protein that controls vascular permeability and inflammatory gene expression. Therefore, we hypothesized that siderophore secretion byK. pneumoniaedirectly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections withtonBmutants that persistin vivobut are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion byK. pneumoniaeinduces the secretion of interleukin-6 (IL-6), CXCL1, and CXCL2, as well as bacterial dissemination to the spleen, compared to siderophore-negative mutants at an equivalent bacterial number. Furthermore, we determined that siderophore-secretingK. pneumoniaestabilized HIF-1αin vivoand that bacterial dissemination to the spleen required alveolar epithelial HIF-1α. Our results indicate that siderophores act directly on the host to induce inflammatory cytokines and bacterial dissemination and that HIF-1α is a susceptibility factor for bacterial invasion during pneumonia.

IMPORTANCEKlebsiella pneumoniaecauses a wide range of bacterial diseases, including pneumonia, urinary tract infections, and sepsis. To cause infection,K. pneumoniaesteals iron from its host by secreting siderophores, small iron-chelating molecules. Classically, siderophores are thought to worsen infections by promoting bacterial growth. In this study, we determined that siderophore-secretingK. pneumoniaecauses lung inflammation and bacterial dissemination to the bloodstream independently of bacterial growth. Furthermore, we determined that siderophore-secretingK. pneumoniaeactivates a host protein, hypoxia inducible factor (HIF)-1α, and requires it for siderophore-dependent bacterial dissemination. Although HIF-1α can protect against some infections, it appears to worsen infection withK. pneumoniae. Together, these results indicate that bacterial siderophores directly alter the host response to pneumonia in addition to providing iron for bacterial growth. Therapies that disrupt production of siderophores could provide a two-pronged attack againstK. pneumoniaeinfection by preventing bacterial growth and preventing bacterial dissemination to the blood.