Klebsiella pneumoniae Siderophores Induce Inflammation, Bacterial Dissemination, and HIF-1α Stabilization during Pneumonia

Abstract

Klebsiella pneumoniae is a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance. K. pneumoniae requires secretion of siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of siderophores secreted by K. pneumoniae during 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 by K. pneumoniae directly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections with tonB mutants that persist in vivo but are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion by K. pneumoniae induces 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-secreting K. pneumoniae stabilized HIF-1α in vivo and 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.

Impact of Klebsiella pneumoniae in lower gastrointestinal tract diseases

“…The ability of a bacterium to secrete more than one type of siderophore enhances its ability to colonize the GIT and prevent neutralization of one siderophore by the host. The most prevalent siderophore secreted by K. pneumoniae is enterobactin due to its high affinity for iron …”

“…The colibactin toxin that is released from K. pneumoniae is mediated by the polyketide synthases ( PKS ) gene. The colibactin toxin is known to cause DNA double‐strand breaks which induce genomic instability as well as cell cycle arrest . Similarly, the continuous insult of the colibactin toxin supplemented with the influx of proinflammatory cytokines into the colonic microenvironment leads to chronic inflammation.…”

“…The most prevalent siderophore secreted by K. pneumoniae is enterobactin due to its high affinity for iron. 50,51 Another component of K. pneumoniae virulence is the lipopolysaccharide (LPS), an endotoxin responsible for protecting the bacteria against host humoral defenses. 52 It is comprised of an O antigen, a core oligosaccharide and lipid A.…”

Modeling Acinetobacter baumannii wound infections

“…Additionally, pathogenic bacteria have been shown to recognize HIF1α and respond to its accumulation with enhanced virulence (29) and to further enhance HIF1α production in host tissues (46, 47). As such, the accumulation of HIF1α in our model may serve as a quorum sensing signal for A. baumannii , enhancing its virulence and leading to wound infection.…”

Siderophores: More than Stealing Iron

“…Previously, Holden et al demonstrated that enterobactin stabilizes HIF-1α in respiratory cells in vitro , thereby inducing expression of proinflammatory cytokines and enhancing lipocalin-2-mediated inflammation (16). In a more recently published mBio article by Holden et al (17), the authors hypothesized that siderophores secreted by K. pneumoniae during lung infection can also have proinflammatory effects by interacting with host cells, thereby promoting pathogenicity during pneumonia.…”