Siderophores Induce Pneumonia-Promoting Changes in Lung Tissue

Siderophores, which are small, high-affinity iron chelating compounds secreted by some types of microorganisms, were found to act directly on the host to induce inflammatory cytokines and to aid in bacterial dissemination.

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 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.


To better analyze the impact of siderophores on K. pneumoniae infections, investigators at the University of Michigan (Ann Arbor, USA) worked with a strain of K. pneumoniae that made three siderophores, enterobactin (Ent), salmochelin (Sal), and yersiniabactin (Ybt) and with a mutant strain that could not produce siderophores.

The investigators reported in the September 13, 2016, online edition of the journal mBio that using a mouse model of pneumonia, they had found that siderophore secretion by K. pneumoniae induced 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, they determined that siderophore-secreting K. pneumoniae stabilized HIF-1alpha in vivo and that bacterial dissemination to the spleen required alveolar epithelial HIF-1alpha. HIF-1alpha (hypoxia inducible factor-1alpha) is a master transcription factor that controls vascular permeability and inflammatory gene expression.

"We have known for a long time that siderophores are critical for bacteria to cause infection, because they steal iron from the host to grow," said senior author Dr. Michael Bachman, assistant professor of clinical at the University of Michigan. "This study sheds some light on the consequences of that. When the bacterium steals this iron, what is likely happening is the host cells are becoming stressed and are inducing inflammation and cell signaling pathways that actually worsen the infection by allowing the bacteria to escape from the lungs to the spleen."

"We had assumed that siderophores simply helped the bacteria grow more, triggering more inflammation and spread," said Dr. Bachman. "Now we know siderophores can trigger these effects directly. 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 against K. pneumoniae infection by preventing bacterial growth and preventing bacterial dissemination to the blood."

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