Impact of CF Therapies on the Pathogenesis of Aspergillus Fumigatus

Project Leader

Robert A. Cramer, Ph.D.
Associate Professor of Microbiology and Immunology
Geisel School of Medicine at Dartmouth

Collaborating Faculty

Alex H. Gifford, M.D.
Assistant Professor of Medicine
Geisel School of Medicine at Dartmouth

A generation ago Cystic Fibrosis (CF) was a disease of early childhood mortality. Thanks to basic and clinical research a child born today with CF has a life expectancy into their 50s. These advances in care of CF patients have come with new clinical challenges most commonly the chronic presence of microbes in the airway that drive morbidity and mortality through lung destruction. As patients now live longer, it has become increasingly recognized that pathogenic fungi such as the mold Aspergillus fumigatus play a pathological role in poor CF disease outcomes. Yet, our understanding of A. fumigatus pathogenesis mechanisms in CF patients is severely limited and needs significant attention given that up to 57% of CF patients can culture positive for A. fumigatus with increasing frequency with age and respiratory function decline. A major frontline treatment for patients suffering from Aspergillus related disease in CF is oral steroid treatment. Steroids appear to provide significance clinical benefit although this has never been validated in a randomized clinical trial for CF patients. Perhaps not surprisingly, it has been observed that only 56% of CF patients with allergic bronchopulmonary aspergillosis are prescribed steroids mostly due to fears of immune suppression and increases in fungal virulence. Thus, research examining the efficacy and impact of steroid treatment on A. fumigatus pathogenesis is urgently needed to help inform better treatment decisions in CF. In addition to oral steroids, recent advances in the development of CFTR potentiators and correctors are revolutionizing the treatment of CF. As patient lung function and life is prolonged with new therapies, it is unknown how these changes to the lung environment will affect the pathogenesis of existing microbial infections. Intriguingly, as a fellow eukaryote, A. fumigatus contains up to 4 potential CFTR homologs in its genome sequence suggesting that its pathogenesis and physiology could be altered in patients on potentiator therapies. Thus, the objective of this CF RDP pilot project is to define the impact of current CF treatments on the pathogenesis of A. fumigatus. Our proposed studies have potential to directly inform clinical care of CF patients by providing new information on the effect of existing and new CF therapies on the virulence of an increasingly common CF pathogen.

Publications
Robert A. Cramer: Pubmed
Alex Gifford: Pubmed