ABSTRACT
Our immune system possesses sophisticated mechanisms to cope with invading microorganisms, while pathogens evolve strategies to deal with threats imposed by host immunity. Human plasma protein α1-antitrypsin (AAT) exhibits pleiotropic immune-modulating properties by both preventing immunopathology and improving antimicrobial host defence. Genetic associations suggested a role for AAT in candidemia, the most frequent fungal blood stream infection in intensive care units, yet little is known about how AAT influences interactions between Candida albicans and the immune system. Here, we show that AAT differentially impacts fungal killing by innate phagocytes. We observed that AAT induces fungal transcriptional reprogramming, associated with cell wall remodelling and downregulation of filamentation repressors. At low concentrations, the cell-wall remodelling induced by AAT increased immunogenic β-glucan exposure and consequently improved fungal clearance by monocytes. Contrastingly, higher AAT concentrations led to excessive C. albicans filamentation and thus promoted fungal immune escape from monocytes and macrophages. This underscores that fungal adaptations to the host protein AAT can differentially define the outcome of encounters with innate immune cells, either contributing to improved immune recognition or fungal immune escape.
Acknowledgements
We acknowledge Sascha Brunke for assistance with microarray analysis. We thank Christoph Becker for the kind provision of Gsdmd-/- mice. We acknowledge Ceren Oktay and Kira Skurk for research support.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data Availability statement
All metadata to replicate the findings of this study are provided in the methods, and data will be made available upon request unless this compromises blood donor anonymity. The microarray dataset generated in this study has been deposited in GEO Series accession number GSE165326 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE165326).
Author contributions
MJ: Conceptualization, Formal analysis, Investigation, Writing – Original Draft, Visualization AD: Validation, Formal analysis, Investigation, Writing – Original Draft, Visualization SA: Validation, Investigation, Visualization SD: Investigation PP: Investigation LV: Resources RJAM: Investigation EGGS: Investigation JR: Resources SW: Resources TA: Investigation, Validation, Writing – Review & Editing LABJ: Conceptualization, Methodology, Resources, Writing – Review & Editing, Supervision BH: Methodology, Resources, Writing – Review & Editing, Supervision MGN: Conceptualization, Methodology, Resources, Writing – Review & Editing, Supervision CAD: Conceptualization, Methodology, Resources, Writing – Original Draft, Supervision, Project administration MSG: Conceptualization, Formal analysis, Investigation, Writing – Original Draft, Visualization, Supervision, Project administration, Funding acquisition
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/21505594.2024.2333367