Single-cell transcriptomics reveals subset-specific metabolic profiles underpinning the bronchial epithelial response to flagellin
Ivan Ramirez-Moral,
Alex R. Schuurman,
Christine C.A. van Linge,
Joe M. Butler,
Xiao Yu,
Karen de Haan,
Sarah van Leeuwen,
Alex F. de Vos,
Menno D. de Jong,
Felipe A. Vieira Braga,
Tom van der Poll
Affiliations
Ivan Ramirez-Moral
Center of Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Alex R. Schuurman
Center of Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Christine C.A. van Linge
Center of Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Joe M. Butler
Center of Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Xiao Yu
Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Karen de Haan
Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Sarah van Leeuwen
Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Alex F. de Vos
Center of Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Menno D. de Jong
Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Felipe A. Vieira Braga
Laboratory for Experimental Oncology and Radiobiology, Center of Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands
Tom van der Poll
Center of Experimental and Molecular Medicine, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Division of Infectious Diseases, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Corresponding author
Summary: Airway epithelial cells represent the first line of defense against respiratory pathogens. Flagellin drives the motility of many mucosal pathogens and has been suggested as an immune enhancing adjunctive therapeutic in infections of the airways. This study leveraged single-cell RNA sequencing to determine cell-specific effects of flagellin in primary human bronchial epithelial cells growing in air-liquid interface. Seven cell clusters were identified, including ciliated cells, ionocytes, and several states of basal and secretory cells, of which only inflammatory basal cells and inflammatory secretory cells demonstrated a proportional increase in response to flagellin. Inflammatory secretory cells showed evidence of metabolic reprogramming toward aerobic glycolysis, while in inflammatory basal cells transcriptome profiles indicated enhanced oxidative phosphorylation. Inhibition of mTOR prevented the shift to glycolysis and reduced inflammatory gene transcription specifically in inflammatory secretory cells. These data demonstrate the functional heterogeneity of the human airway epithelium upon exposure to flagellin.
