Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia
Abstract Staphylococcus aureus is a leading cause of healthcare-associated pneumonia, contributing significantly to morbidity and mortality worldwide. As a ubiquitous colonizer of the upper respiratory tract, S. aureus must undergo substantial metabolic adaptation to achieve persistent infection in...
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2025-08-01
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| Online Access: | https://doi.org/10.1038/s41467-025-62453-y |
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| author | Ying-Tsun Chen Zihua Liu Dario Fucich Stefano G. Giulieri Zhe Liu Ridhima Wadhwa Gustavo Rios Henning Henschel Nupur Tyagi Françios A. B. Olivier Ian R. Monk Shivang S. Shah Shwetha H. Sridhar Marija Drikic Colleen Bianco Gaurav K. Lohia Ayesha Z. Beg Paul J. Planet Ian A. Lewis Robert Sebra Ana Traven Abderrahman Hachani Timothy P. Stinear Benjamin P. Howden Jeffrey M. Boyd Sebastian A. Riquelme Chu Wang Alice Prince Tania Wong Fok Lung |
| author_facet | Ying-Tsun Chen Zihua Liu Dario Fucich Stefano G. Giulieri Zhe Liu Ridhima Wadhwa Gustavo Rios Henning Henschel Nupur Tyagi Françios A. B. Olivier Ian R. Monk Shivang S. Shah Shwetha H. Sridhar Marija Drikic Colleen Bianco Gaurav K. Lohia Ayesha Z. Beg Paul J. Planet Ian A. Lewis Robert Sebra Ana Traven Abderrahman Hachani Timothy P. Stinear Benjamin P. Howden Jeffrey M. Boyd Sebastian A. Riquelme Chu Wang Alice Prince Tania Wong Fok Lung |
| author_sort | Ying-Tsun Chen |
| collection | DOAJ |
| description | Abstract Staphylococcus aureus is a leading cause of healthcare-associated pneumonia, contributing significantly to morbidity and mortality worldwide. As a ubiquitous colonizer of the upper respiratory tract, S. aureus must undergo substantial metabolic adaptation to achieve persistent infection in the distinctive microenvironment of the lung. We observed that fumC, which encodes the enzyme that converts fumarate to malate, is highly conserved with low mutation rates in S. aureus isolates from chronic lung infections. Fumarate, a pro-inflammatory metabolite produced by macrophages during infection, is regulated by the host fumarate hydratase (FH) to limit inflammation. Here, we demonstrate that fumarate, which accumulates in the chronically infected lung, is detrimental to S. aureus, blocking primary metabolic pathways such as glycolysis and oxidative phosphorylation (OXPHOS). This creates a metabolic bottleneck that drives staphylococcal FH (FumC) activity for airway adaptation. FumC not only degrades fumarate but also directs its utilization into critical pathways including the tricarboxylic acid (TCA) cycle, gluconeogenesis and hexosamine synthesis to maintain metabolic fitness and form a protective biofilm. Itaconate, another abundant immunometabolite in the infected airway enhances FumC activity, in synergy with fumarate. In a mouse model of pneumonia, a ΔfumC mutant displays significant attenuation compared to its parent and complemented strains, particularly in fumarate- and itaconate-replete conditions. Our findings underscore the pivotal role of immunometabolites in promoting S. aureus pulmonary adaptation. |
| format | Article |
| id | doaj-art-bade45034a9d4c73afc2f8cd0bda56f0 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-bade45034a9d4c73afc2f8cd0bda56f02025-08-20T03:05:09ZengNature PortfolioNature Communications2041-17232025-08-0116111510.1038/s41467-025-62453-yRegulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumoniaYing-Tsun Chen0Zihua Liu1Dario Fucich2Stefano G. Giulieri3Zhe Liu4Ridhima Wadhwa5Gustavo Rios6Henning Henschel7Nupur Tyagi8Françios A. B. Olivier9Ian R. Monk10Shivang S. Shah11Shwetha H. Sridhar12Marija Drikic13Colleen Bianco14Gaurav K. Lohia15Ayesha Z. Beg16Paul J. Planet17Ian A. Lewis18Robert Sebra19Ana Traven20Abderrahman Hachani21Timothy P. Stinear22Benjamin P. Howden23Jeffrey M. Boyd24Sebastian A. Riquelme25Chu Wang26Alice Prince27Tania Wong Fok Lung28Department of Pediatrics, Columbia UniversityPeking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking UniversityDepartment of Pediatrics, Columbia UniversityDepartment of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and ImmunitySynthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking UniversityDepartment of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical SchoolDepartment of Biochemistry and Microbiology, Rutgers UniversityDepartment of Medicinal Chemistry, Uppsala UniversityDepartment of Biochemistry and Microbiology, Rutgers UniversityInfection Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash UniversityDepartment of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and ImmunityDepartment of Pediatrics, Columbia UniversityDepartment of Genetics and Genomic Sciences, Mt. Sinai Icahn School of MedicineDepartment of Biological Sciences, University of CalgaryDivision of Infectious Disease, Department of Pediatrics, The Children’s Hospital of PhiladelphiaDepartment of Pediatrics, Columbia UniversityDepartment of Pediatrics, Columbia UniversityDivision of Infectious Disease, Department of Pediatrics, The Children’s Hospital of PhiladelphiaDepartment of Biological Sciences, University of CalgaryDepartment of Genetics and Genomic Sciences, Mt. Sinai Icahn School of MedicineInfection Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash UniversityDepartment of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and ImmunityDepartment of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and ImmunityDepartment of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and ImmunityDepartment of Biochemistry and Microbiology, Rutgers UniversityDepartment of Pediatrics, Columbia UniversityPeking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking UniversityDepartment of Pediatrics, Columbia UniversityDepartment of Pediatrics, Columbia UniversityAbstract Staphylococcus aureus is a leading cause of healthcare-associated pneumonia, contributing significantly to morbidity and mortality worldwide. As a ubiquitous colonizer of the upper respiratory tract, S. aureus must undergo substantial metabolic adaptation to achieve persistent infection in the distinctive microenvironment of the lung. We observed that fumC, which encodes the enzyme that converts fumarate to malate, is highly conserved with low mutation rates in S. aureus isolates from chronic lung infections. Fumarate, a pro-inflammatory metabolite produced by macrophages during infection, is regulated by the host fumarate hydratase (FH) to limit inflammation. Here, we demonstrate that fumarate, which accumulates in the chronically infected lung, is detrimental to S. aureus, blocking primary metabolic pathways such as glycolysis and oxidative phosphorylation (OXPHOS). This creates a metabolic bottleneck that drives staphylococcal FH (FumC) activity for airway adaptation. FumC not only degrades fumarate but also directs its utilization into critical pathways including the tricarboxylic acid (TCA) cycle, gluconeogenesis and hexosamine synthesis to maintain metabolic fitness and form a protective biofilm. Itaconate, another abundant immunometabolite in the infected airway enhances FumC activity, in synergy with fumarate. In a mouse model of pneumonia, a ΔfumC mutant displays significant attenuation compared to its parent and complemented strains, particularly in fumarate- and itaconate-replete conditions. Our findings underscore the pivotal role of immunometabolites in promoting S. aureus pulmonary adaptation.https://doi.org/10.1038/s41467-025-62453-y |
| spellingShingle | Ying-Tsun Chen Zihua Liu Dario Fucich Stefano G. Giulieri Zhe Liu Ridhima Wadhwa Gustavo Rios Henning Henschel Nupur Tyagi Françios A. B. Olivier Ian R. Monk Shivang S. Shah Shwetha H. Sridhar Marija Drikic Colleen Bianco Gaurav K. Lohia Ayesha Z. Beg Paul J. Planet Ian A. Lewis Robert Sebra Ana Traven Abderrahman Hachani Timothy P. Stinear Benjamin P. Howden Jeffrey M. Boyd Sebastian A. Riquelme Chu Wang Alice Prince Tania Wong Fok Lung Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia Nature Communications |
| title | Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia |
| title_full | Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia |
| title_fullStr | Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia |
| title_full_unstemmed | Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia |
| title_short | Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia |
| title_sort | regulation of airway fumarate by host and pathogen promotes staphylococcus aureus pneumonia |
| url | https://doi.org/10.1038/s41467-025-62453-y |
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