Molecules released by Klebsiella pneumoniae bacterium pave the way for invasive infection

In mice infected with K. pneumoniae, the investigators found, siderophores caused the animals to turn on proteins that increase inflammation and activated a master protein called HIF-1 alpha that paved the way for bacteria to spread from the lungs to the spleen. HIF-1 alpha controls the ability of substances to pass through blood vessels and is involved in the immune response.

"We've 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 study author Michael Bachman, M.D., Ph.D., assistant professor of clinical pathology and associate director of the Clinical Microbiology Laboratory at the University of Michigan in Ann Arbor. "This study sheds some light on the consequences of that. When the bacterium steals this iron, what's 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."

K. pneumoniae can cause a wide range of infections, including pneumonia, bacteremia, wound or surgical site infections and urinary tract infections. Klebsiella are estimated to be the third most common cause of hospital-acquired infections in the United States, Bachman said. The bacterium is rapidly becoming resistant to all known antibiotics, therefore becoming more difficult to treat. Resistant forms are considered an urgent threat to public health by the federal Centers for Disease Control and Prevention.

For the study, Bachman and colleagues infected mice with either a strain of K. pneumoniae that makes three siderophores called enterobactin (Ent), salmochelin (Sal) and yersiniabactin (Ybt), or a mutant form of the bacterium that could not produce siderophores. Mice infected with the siderophore-producing strain had about 100 times the number of bacteria in their lungs as those infected with the mutant bacterium; they also had more bacteria invading from the lung to the spleen and they activated proteins involved in inflammation.

"We had assumed that siderophores simply helped the bacteria grow more, triggering more inflammation and spread," Bachman said. "Now we know siderophores can trigger these effects directly."

Additional laboratory experiments in mice revealed that all three siderophores were required for the most bacterial dissemination to the spleen; that siderophores secreted by K. pneumoniae stabilized HIF-1 alpha; and that HIF-1 alpha in the cells lining the lungs is required for the bacteria to spread to the spleen. Mice that produced HIF-1 alpha and were infected with K. pneumoniae had more bacterial invasion to the spleen than mice that did not produce HIF-1 alpha and were similarly infected.

"These results indicate that bacterial siderophores directly alter the host response to pneumonia in addition to providing iron for bacterial growth," Bachman said. "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."