Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia

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 and Tania Wong Fok Lung ()
Additional contact information
Ying-Tsun Chen: Columbia University
Zihua Liu: Peking University
Dario Fucich: Columbia University
Stefano G. Giulieri: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Zhe Liu: Peking University
Ridhima Wadhwa: Rutgers New Jersey Medical School
Gustavo Rios: Rutgers University
Henning Henschel: Uppsala University
Nupur Tyagi: Rutgers University
Françios A. B. Olivier: Monash University
Ian R. Monk: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Shivang S. Shah: Columbia University
Shwetha H. Sridhar: Mt. Sinai Icahn School of Medicine
Marija Drikic: University of Calgary
Colleen Bianco: The Children’s Hospital of Philadelphia
Gaurav K. Lohia: Columbia University
Ayesha Z. Beg: Columbia University
Paul J. Planet: The Children’s Hospital of Philadelphia
Ian A. Lewis: University of Calgary
Robert Sebra: Mt. Sinai Icahn School of Medicine
Ana Traven: Monash University
Abderrahman Hachani: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Timothy P. Stinear: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Benjamin P. Howden: The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Jeffrey M. Boyd: Rutgers University
Sebastian A. Riquelme: Columbia University
Chu Wang: Peking University
Alice Prince: Columbia University
Tania Wong Fok Lung: Columbia University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62453-y

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