Aspergillus fumigatus secondary metabolite pyripyropene is important for the dual biofilm formation with Pseudomonas aeruginosa
ABSTRACT The human pathogenic fungus Aspergillus fumigatus establishes dual biofilm interactions in the lungs with the pathogenic bacterium Pseudomonas aeruginosa. Screening of 21 A. fumigatus null mutants revealed seven mutants (two G protein-coupled receptors, three mitogen-activated protein kinas...
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American Society for Microbiology
2025-04-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00363-25 |
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| author | Patricia Alves de Castro Daniel Yuri Akiyama Camila Figueiredo Pinzan Thaila Fernanda dos Reis Endrews Delbaje Peter Rocha Mario Augusto Izidoro Sérgio Schenkman Shinya Sugimoto Norio Takeshita Karin Steffen Jessica L. Aycock Stephen K. Dolan Antonis Rokas Taícia Fill Gustavo H. Goldman |
| author_facet | Patricia Alves de Castro Daniel Yuri Akiyama Camila Figueiredo Pinzan Thaila Fernanda dos Reis Endrews Delbaje Peter Rocha Mario Augusto Izidoro Sérgio Schenkman Shinya Sugimoto Norio Takeshita Karin Steffen Jessica L. Aycock Stephen K. Dolan Antonis Rokas Taícia Fill Gustavo H. Goldman |
| author_sort | Patricia Alves de Castro |
| collection | DOAJ |
| description | ABSTRACT The human pathogenic fungus Aspergillus fumigatus establishes dual biofilm interactions in the lungs with the pathogenic bacterium Pseudomonas aeruginosa. Screening of 21 A. fumigatus null mutants revealed seven mutants (two G protein-coupled receptors, three mitogen-activated protein kinase receptors, a Gα protein, and one histidine kinase receptor) with reduced biofilm formation, specifically in the presence of P. aeruginosa. Transcriptional profiling and metabolomics analysis of secondary metabolites produced by one of these mutants, ΔgpaB (gpaB encodes a Gα protein), showed GpaB controls the production of several important metabolites for the dual biofilm interaction, including pyripyropene A, a potent inhibitor of mammalian acyl-CoA cholesterol acyltransferase. Deletion of pyr2, encoding a non-reducing polyketide synthase essential for pyripyropene biosynthesis, showed reduced A. fumigatus Δpyr2-P. aeruginosa biofilm growth, altered macrophage responses, and attenuated mouse virulence in a chemotherapeutic murine model. We identified pyripyropene as a novel player in the ecology and pathogenic interactions of this important human fungal pathogen.IMPORTANCEAspergillus fumigatus and Pseudomonas aeruginosa are two important human pathogens. Both organisms establish biofilm interactions in patients affected with chronic lung pulmonary infections, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease. Colonization with A. fumigatus is associated with an increased risk of P. aeruginosa colonization in CF patients, and disease prognosis is poor when both pathogens are present. Here, we identified A. fumigatus genetic determinants important for the establishment of in vitro dual A. fumigatus-P. aeruginosa biofilm interactions. Among them, an A. fumigatus Gα protein GpaB is important for this interaction controlling the production of the secondary metabolite pyripyropene. We demonstrate that the lack of pyripyropene production decreases the dual biofilm interaction between the two species as well as the virulence of A. fumigatus in a chemotherapeutic murine model of aspergillosis. These results reveal a complete novel role for this secondary metabolite in the ecology and pathogenic interactions of this important human fungal pathogen. |
| format | Article |
| id | doaj-art-c907526d3c67455b9a504ea817d05f3d |
| institution | OA Journals |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | American Society for Microbiology |
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| spelling | doaj-art-c907526d3c67455b9a504ea817d05f3d2025-08-20T02:07:59ZengAmerican Society for MicrobiologymBio2150-75112025-04-0116410.1128/mbio.00363-25Aspergillus fumigatus secondary metabolite pyripyropene is important for the dual biofilm formation with Pseudomonas aeruginosaPatricia Alves de Castro0Daniel Yuri Akiyama1Camila Figueiredo Pinzan2Thaila Fernanda dos Reis3Endrews Delbaje4Peter Rocha5Mario Augusto Izidoro6Sérgio Schenkman7Shinya Sugimoto8Norio Takeshita9Karin Steffen10Jessica L. Aycock11Stephen K. Dolan12Antonis Rokas13Taícia Fill14Gustavo H. Goldman15Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, BrazilInstituto de Química, Universidade Estadual de Campinas, Campinas, BrazilFaculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, BrazilFaculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, BrazilFaculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, BrazilFaculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, BrazilHospital São Paulo, Vila Clementino, São Paulo, BrazilDepartamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, BrazilDepartment of Bacteriology, Jikei Center for Biofilm Science and Technology, Laboratory of Amyloid Regulation, The Jikei University School of Medicine, Tokyo, JapanMicrobiology Research Center for Sustainability (MiCS), Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, JapanDepartment of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USADepartment of Genetics and Biochemistry, Eukaryotic Pathogens Innovation Center, Clemson University, Clemson, South Carolina, USADepartment of Genetics and Biochemistry, Eukaryotic Pathogens Innovation Center, Clemson University, Clemson, South Carolina, USADepartment of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USAInstituto de Química, Universidade Estadual de Campinas, Campinas, BrazilFaculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, BrazilABSTRACT The human pathogenic fungus Aspergillus fumigatus establishes dual biofilm interactions in the lungs with the pathogenic bacterium Pseudomonas aeruginosa. Screening of 21 A. fumigatus null mutants revealed seven mutants (two G protein-coupled receptors, three mitogen-activated protein kinase receptors, a Gα protein, and one histidine kinase receptor) with reduced biofilm formation, specifically in the presence of P. aeruginosa. Transcriptional profiling and metabolomics analysis of secondary metabolites produced by one of these mutants, ΔgpaB (gpaB encodes a Gα protein), showed GpaB controls the production of several important metabolites for the dual biofilm interaction, including pyripyropene A, a potent inhibitor of mammalian acyl-CoA cholesterol acyltransferase. Deletion of pyr2, encoding a non-reducing polyketide synthase essential for pyripyropene biosynthesis, showed reduced A. fumigatus Δpyr2-P. aeruginosa biofilm growth, altered macrophage responses, and attenuated mouse virulence in a chemotherapeutic murine model. We identified pyripyropene as a novel player in the ecology and pathogenic interactions of this important human fungal pathogen.IMPORTANCEAspergillus fumigatus and Pseudomonas aeruginosa are two important human pathogens. Both organisms establish biofilm interactions in patients affected with chronic lung pulmonary infections, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease. Colonization with A. fumigatus is associated with an increased risk of P. aeruginosa colonization in CF patients, and disease prognosis is poor when both pathogens are present. Here, we identified A. fumigatus genetic determinants important for the establishment of in vitro dual A. fumigatus-P. aeruginosa biofilm interactions. Among them, an A. fumigatus Gα protein GpaB is important for this interaction controlling the production of the secondary metabolite pyripyropene. We demonstrate that the lack of pyripyropene production decreases the dual biofilm interaction between the two species as well as the virulence of A. fumigatus in a chemotherapeutic murine model of aspergillosis. These results reveal a complete novel role for this secondary metabolite in the ecology and pathogenic interactions of this important human fungal pathogen.https://journals.asm.org/doi/10.1128/mbio.00363-25Aspergillus fumigatusPseudomonas aeruginosabiofilm formationG-protein signalingsecondary metabolitespyripyropene |
| spellingShingle | Patricia Alves de Castro Daniel Yuri Akiyama Camila Figueiredo Pinzan Thaila Fernanda dos Reis Endrews Delbaje Peter Rocha Mario Augusto Izidoro Sérgio Schenkman Shinya Sugimoto Norio Takeshita Karin Steffen Jessica L. Aycock Stephen K. Dolan Antonis Rokas Taícia Fill Gustavo H. Goldman Aspergillus fumigatus secondary metabolite pyripyropene is important for the dual biofilm formation with Pseudomonas aeruginosa mBio Aspergillus fumigatus Pseudomonas aeruginosa biofilm formation G-protein signaling secondary metabolites pyripyropene |
| title | Aspergillus fumigatus secondary metabolite pyripyropene is important for the dual biofilm formation with Pseudomonas aeruginosa |
| title_full | Aspergillus fumigatus secondary metabolite pyripyropene is important for the dual biofilm formation with Pseudomonas aeruginosa |
| title_fullStr | Aspergillus fumigatus secondary metabolite pyripyropene is important for the dual biofilm formation with Pseudomonas aeruginosa |
| title_full_unstemmed | Aspergillus fumigatus secondary metabolite pyripyropene is important for the dual biofilm formation with Pseudomonas aeruginosa |
| title_short | Aspergillus fumigatus secondary metabolite pyripyropene is important for the dual biofilm formation with Pseudomonas aeruginosa |
| title_sort | aspergillus fumigatus secondary metabolite pyripyropene is important for the dual biofilm formation with pseudomonas aeruginosa |
| topic | Aspergillus fumigatus Pseudomonas aeruginosa biofilm formation G-protein signaling secondary metabolites pyripyropene |
| url | https://journals.asm.org/doi/10.1128/mbio.00363-25 |
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