Alpha1-antitrypsin impacts innate host–pathogen interactions with Candida albicans by stimulating fungal filamentation
Martin Jaeger,
Axel Dietschmann,
Sophie Austermeier,
Sude Dinçer,
Pauline Porschitz,
Larsen Vornholz,
Ralph J.A. Maas,
Evelien G.G. Sprenkeler,
Jürgen Ruland,
Stefan Wirtz,
Tania Azam,
Leo A.B. Joosten,
Bernhard Hube,
Mihai G. Netea,
Charles A. Dinarello,
Mark S. Gresnigt
Affiliations
Martin Jaeger
Department of Medicine, University of Colorado Denver, Aurora, USA
Axel Dietschmann
Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Jena, Germany
Sophie Austermeier
Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Jena, Germany
Sude Dinçer
Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Jena, Germany
Pauline Porschitz
Junior Research Group Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Jena, Germany
Larsen Vornholz
Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine and Health, Center for Translational Cancer Research (TranslaTUM), Munich, Germany
Ralph J.A. Maas
Department of Medicine, University of Colorado Denver, Aurora, USA
Evelien G.G. Sprenkeler
Department of Internal Medicine, Radboud University Medical Center and Radboud Center for Infectious diseases (RCI), Nijmegen, the Netherlands
Jürgen Ruland
Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine and Health, Center for Translational Cancer Research (TranslaTUM), Munich, Germany
Department of Medicine, University of Colorado Denver, Aurora, USA
Leo A.B. Joosten
Department of Internal Medicine, Radboud University Medical Center and Radboud Center for Infectious diseases (RCI), Nijmegen, the Netherlands
Bernhard Hube
Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Jena, Germany
Mihai G. Netea
Department of Internal Medicine, Radboud University Medical Center and Radboud Center for Infectious diseases (RCI), Nijmegen, the Netherlands
Charles A. Dinarello
Department of Medicine, University of Colorado Denver, Aurora, USA
Mark S. Gresnigt
Department of Medicine, University of Colorado Denver, Aurora, USA
ABSTRACTOur 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.
