New research links the chronic lung inflammation that is a hallmark of cystic fibrosis with a new class of bacterial enzymes that hijack the patient’s immune response and prevent the body from calling of runaway inflammation.
Results from the laboratory investigation appear in the Proceedings of the National Academy of Sciences and give scientists two avenues to explore for the creation of therapies that could interrupt or correct this interference by the opportunistic bacterium Pseudomonas aeruginosa, which disproportionately infects people with cystic fibrosis.
“There are about 30,000 patients in the US with cystic fibrosis, and hundreds of thousands more with other chronic lung diseases. Once these diseases progress to the point that the patient is chronically infected with P. aeruginosa, current antimicrobial therapies are no longer effective and there are very few treatment options left,” says Jennifer M. Bomberger, assistant professor in the University of Pittsburgh’s School of Medicine’s microbiology and molecular genetics and senior author of the study.
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“Lung damage from these chronic P. aeruginosa infections, coupled with a robust but unproductive inflammatory response to the infection, will eventually lead to respiratory failure in the patient and the need for a lung transplant.”
Cystic fibrosis results from a genetic mutation that makes it difficult for patients to clear infections, allowing microorganisms to repeatedly infect the respiratory tract. By the time they reach adulthood, most cystic fibrosis patients are chronically infected with P. aeruginosa because this particular bacterium has an exceptional ability to outcompete other microorganisms and establish a stronghold in the lungs.
Aiding its ability to outfight other infections, P. aeruginosa thrives when the body creates an inflammatory response aimed at isolating foreign invaders and attracting white blood cells to fight them. The body’s own inflammatory response to fight infection is a major part of what actually damages a cystic fibrosis patient’s lungs to the point that they no longer function.
Bomberger’s team, in collaboration with Dean Madden of the Geisel School of Medicine at Dartmouth, discovered that P. aeruginosa perpetuates inflammation by secreting an enzyme called Cif that sabotages the body’s ability to make a key molecule called a “pro-resolving lipid mediator” and put a stop to the inflammatory response it started.
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The scientists confirmed this mechanism by analyzing secretions drawn from the lungs of cystic fibrosis patients seen at Children’s Hospital of Pittsburgh of UPMC and linking their findings to patient records. Patients with higher Cif levels in their lung secretions had reduced biological signaling to stop inflammation and increased levels of IL-8, a marker for inflammation. Increased Cif levels also correlated with reduced lung function, which leads to disease progression in patients.
Previous studies in mice indicated that artificially boosting the levels of the pro-resolving lipid mediator reduces the inflammatory response and promotes clearance of P. aeruginosa in a pneumonia model. Bomberger and Madden, in collaboration with colleagues at the University of California, Davis, are exploring an alternative strategy to inhibit Cif activity, stopping the problem before it begins.
“It will be key to devise a way to remove P. aeruginosa’s ability to capitalize on the body’s natural inflammatory response, without eliminating that response,” says Bomberger. “Inflammation is happening for a reason—to clear infection. We just need it to temper the response when it is not effectively doing its job or is no longer needed.”
Grants from the National Institutes of Health, a Gilead Sciences Research Scholars in Cystic Fibrosis Award, Cystic Fibrosis Foundation grants, and a Munck-Pfefferkorn Award supported the work.
Source: University of Pittsburgh
