title: Redox metabolites signal polymicrobial biofilm development via the NapA oxidative stress cascade in Aspergillus.
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.
authors.affiliation: Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL 60208, USA.
authors.forename: He
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Jaekuk
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biology, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Mathew
authors.initials: M
authors.lastname: Liew
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, IL 60208, USA; Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Yan
authors.affiliation: Department of Chemistry, Northeastern Illinois University, Chicago, IL 60625, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Herrera
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Bok
authors.affiliation: 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.
authors.forename: Neil L
authors.initials: NL
authors.lastname: Kelleher
authors.affiliation: 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.
authors.forename: Nancy P
authors.initials: NP
authors.lastname: Keller
authors.affiliation: Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL 60208, USA. Electronic address: yun-wang@northwestern.edu.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D001232:Aspergillus fumigatus / Q000254:growth & development / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D018441:Biofilms; D018920:Coculture Techniques; D005656:Fungal Proteins / Q000378:metabolism; D005912:Gliotoxin / Q000378:metabolism; D008773:Methylphenazonium Methosulfate; D056265:Microbial Interactions; D018384:Oxidative Stress; D010619:Phenazines / Q000378:metabolism*; D010641:Phenotype; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D013172:Spores, Fungal / Q000254:growth & development
chemical_list: C000601497:5-methylphenazine-1-carboxylic acid; D050976:Basic-Leucine Zipper Transcription Factors; D005656:Fungal Proteins; D010619:Phenazines; C000598831:phenazine; D008773:Methylphenazonium Methosulfate; D005912:Gliotoxin