He Zheng1, Jaekuk Kim2, Mathew Liew3, John K Yan4, Oscar Herrera5, Jin Woo Bok6, Neil L Kelleher7, Nancy P Keller8, Yun Wang9. 1. Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL 60208, USA. 2. Department of Chemistry, Northwestern University, Evanston, IL 60208, USA. 3. Department of Biology, Northwestern University, Evanston, IL 60208, USA. 4. Department of Chemistry, Northwestern University, Evanston, IL 60208, USA; Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA. 5. Department of Chemistry, Northeastern Illinois University, Chicago, IL 60625, USA. 6. Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI 53706, USA. 7. Department of Chemistry, Northwestern University, Evanston, IL 60208, USA; Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA; Feinberg School of Medicine, Northwestern University, Evanston, IL 60208, USA. 8. Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: npkeller@wisc.edu. 9. Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL 60208, USA. Electronic address: yun-wang@northwestern.edu.
Abstract
BACKGROUND: Filamentous fungi and bacteria form mixed-species biofilms in nature and diverse clinical contexts. They secrete a wealth of redox-active small molecule secondary metabolites, which are traditionally viewed as toxins that inhibit growth of competing microbes. RESULTS: Here, we report that these "toxins" can act as interspecies signals, affecting filamentous fungal development via oxidative stress regulation. Specifically, in coculture biofilms, Pseudomonas aeruginosa phenazine-derived metabolites differentially modulated Aspergillus fumigatus development, shifting from weak vegetative growth to induced asexual sporulation (conidiation) along a decreasing phenazine gradient. The A. fumigatus morphological shift correlated with the production of phenazine radicals and concomitant reactive oxygen species (ROS) production generated by phenazine redox cycling. Phenazine conidiation signaling was conserved in the genetic model A. nidulans and mediated by NapA, a homolog of AP-1-like bZIP transcription factor, which is essential for the response to oxidative stress in humans, yeast, and filamentous fungi. Expression profiling showed phenazine treatment induced a NapA-dependent response of the global oxidative stress metabolome, including the thioredoxin, glutathione, and NADPH-oxidase systems. Conidiation induction in A. nidulans by another microbial redox-active secondary metabolite, gliotoxin, also required NapA. CONCLUSIONS: This work highlights that microbial redox metabolites are key signals for sporulation in filamentous fungi, which are communicated through an evolutionarily conserved eukaryotic stress response pathway. It provides a foundation for interspecies signaling in environmental and clinical biofilms involving bacteria and filamentous fungi.
BACKGROUND:Filamentous fungi and bacteria form mixed-species biofilms in nature and diverse clinical contexts. They secrete a wealth of redox-active small molecule secondary metabolites, which are traditionally viewed as toxins that inhibit growth of competing microbes. RESULTS: Here, we report that these "toxins" can act as interspecies signals, affecting filamentous fungal development via oxidative stress regulation. Specifically, in coculture biofilms, Pseudomonas aeruginosaphenazine-derived metabolites differentially modulated Aspergillus fumigatus development, shifting from weak vegetative growth to induced asexual sporulation (conidiation) along a decreasing phenazine gradient. The A. fumigatus morphological shift correlated with the production of phenazine radicals and concomitant reactive oxygen species (ROS) production generated by phenazine redox cycling. Phenazine conidiation signaling was conserved in the genetic model A. nidulans and mediated by NapA, a homolog of AP-1-like bZIP transcription factor, which is essential for the response to oxidative stress in humans, yeast, and filamentous fungi. Expression profiling showed phenazine treatment induced a NapA-dependent response of the global oxidative stress metabolome, including the thioredoxin, glutathione, and NADPH-oxidase systems. Conidiation induction in A. nidulans by another microbial redox-active secondary metabolite, gliotoxin, also required NapA. CONCLUSIONS: This work highlights that microbial redox metabolites are key signals for sporulation in filamentous fungi, which are communicated through an evolutionarily conserved eukaryotic stress response pathway. It provides a foundation for interspecies signaling in environmental and clinical biofilms involving bacteria and filamentous fungi.
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