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

Author

Listed:
  • 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
    The University of Melbourne)

  • Zhe Liu

    (Peking University)

  • Ridhima Wadhwa

    (Rutgers New Jersey Medical School
    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
    The University of Melbourne)

  • 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
    University of Pennsylvania)

  • Ian A. Lewis

    (University of Calgary)

  • Robert Sebra

    (Mt. Sinai Icahn School of Medicine
    Panacent Bio)

  • Ana Traven

    (Monash University)

  • Abderrahman Hachani

    (The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
    The University of Melbourne)

  • Timothy P. Stinear

    (The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
    The University of Melbourne)

  • Benjamin P. Howden

    (The University of Melbourne at the Peter Doherty Institute for Infection and Immunity
    The University of Melbourne
    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
    Peking University)

  • Alice Prince

    (Columbia University)

  • Tania Wong Fok Lung

    (Columbia University
    Rutgers New Jersey Medical School
    Rutgers New Jersey Medical School)

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.

Suggested Citation

  • 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 & Sh, 2025. "Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62453-y
    DOI: 10.1038/s41467-025-62453-y
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