Fungal melanin suppresses airway epithelial chemokine secretion through blockade of calcium fluxing

Author:

Reedy Jennifer L.ORCID,Jensen Kirstine NollingORCID,Crossen Arianne J.ORCID,Basham Kyle J.,Ward Rebecca A.ORCID,Reardon Christopher M.,Brown Harding HannahORCID,Hepworth Olivia W.,Simaku PatriciaORCID,Kwaku Geneva N.,Tone Kazuya,Willment Janet A.,Reid Delyth M.,Stappers Mark H. T.,Brown Gordon D.ORCID,Rajagopal JayarajORCID,Vyas Jatin M.ORCID

Abstract

AbstractRespiratory infections caused by the human fungal pathogen Aspergillus fumigatus are a major cause of mortality for immunocompromised patients. Exposure to these pathogens occurs through inhalation, although the role of the respiratory epithelium in disease pathogenesis has not been fully defined. Employing a primary human airway epithelial model, we demonstrate that fungal melanins potently block the post-translational secretion of the chemokines CXCL1 and CXCL8 independent of transcription or the requirement of melanin to be phagocytosed, leading to a significant reduction in neutrophil recruitment to the apical airway both in vitro and in vivo. Aspergillus-derived melanin, a major constituent of the fungal cell wall, dampened airway epithelial chemokine secretion in response to fungi, bacteria, and exogenous cytokines. Furthermore, melanin muted pathogen-mediated calcium fluxing and hindered actin filamentation. Taken together, our results reveal a critical role for melanin interaction with airway epithelium in shaping the host response to fungal and bacterial pathogens.

Funder

U.S. Department of Health & Human Services | National Institutes of Health

U.S. Department of Health & Human Services | NIH | Center for Information Technology

Wellcome Trust

Publisher

Springer Science and Business Media LLC

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