Disease severity in cystic fibrosis (CF) may be associated with an overreaction of the immune system to the fungus Aspergillus fumigatus, particularly due to a type of white blood cell called a phagocyte — which ingests and kills invading organisms — a study suggests.
U.K. researchers found that phagocytes from CF patients release higher amounts of harmful reactive oxygen species in response to Aspergillus fumigatus, a common cause of lung infection in these patients.
The study, “Aspergillus-induced superoxide production by cystic fibrosis phagocytes is associated with disease severity,” was published in the journal ERC Open Research.
Recent studies have supported the idea that the widespread environmental fungus Aspergillus fumigatus may play a critical role in CF lung disease.
Up to 58% of CF patients are colonized with this fungus, and an estimated 47.7% of adult patients are affected by either allergic reactions or infection caused by the fungus.
Persistent infections with A. fumigatus are also known to be adversely correlated with lung function and hospitalization in CF patients.
Researchers hypothesized that the anti-fungal defense mechanism in CF patients might be altered and have an impact on the progression of lung disease.
To investigate this hypothesis, the team compared the immune response of phagocytes from CF patients with those of healthy individuals used as controls, and tried to correlate them to clinical metrics of disease severity.
To address the anti-fungal activity of phagocytes, these cells were isolated from the blood of patients and healthy donors and assayed in vitro in the presence of the A. fumigatus fungus. Since phagocytes include several types of white blood cells, researchers purified different phagocyte fractions, separating the most prominent types of phagocytes — neutrophils and monocytes.
In general, researchers observed that phagocytes were equally efficient at ingesting and killing fungus cells whether they were from CF patients or healthy individuals.
However, phagocytes from CF patients behaved differently when researchers looked at the release of reactive oxygen species.
Production of reactive oxygen species by phagocytes is a long-known mechanism used by cells to kill harmful organisms. Reactive oxygen species include a number of reactive molecules and free radicals derived from oxygen, which can be produced as byproducts of the normal respiratory metabolism.
Reactive oxygen species have the potential to cause cell damage and eventually lead to cell death. Cells also use them as messengers to communicate signals within or between cells.
Researchers found that all phagocyte fractions collected from CF patients produced significantly higher amounts of reactive oxygen species — three to four times more — in the presence of A. fumigatus than healthy controls.
According to the team, this exacerbated response seen in phagocytes from patients seemed specific to the fungus, since no differences were seen between patients and healthy controls when phagocytes were incubated with the bacteria Pseudomonas aeruginosa, a major cause of lung infections in CF.
Importantly, the excessive amount of reactive oxygen species produced by phagocytes — in particular neutrophils — from CF patients was significantly correlated with a higher number of clinical exacerbations in the previous year and a reduction in lung function.
The worse a patient’s lung function was — measured as the forced expiratory volume in one second (FEV1) — the higher the release of reactive oxygen species from the patient’s phagocytes. Those with an FEV1 equal to or below 50% exhibited increased reactive oxygen species production than those with an FEV1 of more than 50%.
“Our data suggest that a hyperresponsive state in CF phagocytes plays a crucial role in the hyperinflammatory response upon exposure to A. fumigatus,” the researchers wrote.
“New interventions to prevent fungal induced ROS production need to be explored, such as early treatment of Aspergillus infection or targeting the defective molecular pathway underlying these aberrant responses,” they concluded.
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