Abstract
Excessive inflammation by phagocytes during Aspergillus fumigatus infection is thought to promote lung function decline in CF patients. CFTR modulators have been shown to reduce A. fumigatus colonization in vivo, however, their antifungal and anti-inflammatory mechanisms are unclear. Other treatments including azithromycin and acebilustat may dampen Aspergillus-induced inflammation due to their immunomodulatory properties. Therefore, we set out in this study to determine the effects of current CF therapies on ROS production and fungal killing, either direct or indirect by enhancing antifungal immune mechanisms in peripheral blood immune cells from CF patients upon A. fumigatus infection. Isolated peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) from CF patients and healthy volunteers were challenged with A. fumigatus following pre-treatment with CFTR modulators, azithromycin or acebilustat. Ivacaftor/lumacaftor treated CF and control subject PMNs resulted in a significant reduction (p < 0.05) in Aspergillus-induced ROS. For CF PBMC, Aspergillus-induced ROS was significantly reduced when pre-treated with ivacaftor alone (p < 0.01) or in combination with lumacaftor (p < 0.01), with a comparable significant reduction in control subject PBMC (p < 0.05). Azithromycin and acebilustat had no effect on ROS production by CF or control subject phagocytes. None of the treatments showed an indirect or direct antifungal activity. In summary, CFTR modulators have potential for additional immunomodulatory benefits to prevent or treat Aspergillus-induced inflammation in CF. The comparable effects of CFTR modulators observed in phagocytes from control subjects questions their exact mechanism of action.
Highlights
Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder characterized by chronic respiratory infections, progressive respiratory disease and respiratory failure (Elborn, 2016)
Our group previously demonstrated that peripheral blood phagocytes from CF patients show normal antifungal killing in response to A. fumigatus, but that this is associated with excessive reactive oxygen species (ROS) production (Brunel et al, 2018)
We show that the CFTR modulators, ivacaftor, lumacaftor and its combination, are able to downregulate ROS production by human CF phagocytes without compromising their fungal killing ability
Summary
Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder characterized by chronic respiratory infections, progressive respiratory disease and respiratory failure (Elborn, 2016). Our group previously demonstrated that peripheral blood phagocytes from CF patients show normal antifungal killing in response to A. fumigatus, but that this is associated with excessive reactive oxygen species (ROS) production (Brunel et al, 2018). As eradication of A. fumigatus from the airways of CF patients is a huge challenge due to the universal presence of A. fumigatus in the environment, finding ways to dampen Aspergillus-induced inflammation may be more feasible, as long as these strategies do not affect antifungal killing mechanisms. A key objective was to determine in detail the effects of three important CF therapies, azithromycin, acebilustat, and CFTR modulators, on the antifungal immune mechanisms. We present here our results of the effect of these treatments on Aspergillus-induced ROS production and fungal killing, either direct or indirect by enhancing antifungal immune mechanisms in peripheral blood phagocytes
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