Cystic fibrosis (CF) is a life-shortening multisystem hereditary disease caused by abnormal chloride transport. CF lung disease is driven by innate immune dysfunction and exaggerated inflammatory responses that contribute to tissue injury. In order to define the transcriptional profile of this airway immune dysfunction, we performed the first single-cell transcriptome characterization of CF sputum.
To define the transcriptional profile of sputum cells and its implication in the pathogenesis of immune function and the development of CF lung disease.
We performed single-cell RNA sequencing of sputum cells of nine subjects with CF and five healthy controls. We applied novel computational approaches to define expression-based cell function and maturity profiles, here called transcriptional archetypes.
The airway immune cell repertoire shifted from alveolar macrophages in healthy controls to a predominance of recruited monocytes and neutrophils in CF. Recruited lung mononuclear phagocytes were abundant in CF, separated into three archetypes: activated monocytes, monocyte-derived macrophages, and heat-shock activated monocytes. Neutrophils were most prevalent in CF, with a dominant immature pro-inflammatory archetype. While CF monocytes exhibited pro-inflammatory features, both monocytes and neutrophils showed transcriptional evidence of abnormal phagocytic and cell-survival programs.
Our findings offer an opportunity to understand subject-specific immune dysfunction and its contribution to divergent clinical courses in cystic fibrosis. As we progress towards personalized applications of therapeutic and genomic developments, we hope this inflammation profiling approach will enable further discoveries that change the natural history of CF lung disease.