Long-term antibiotic exposure promotes mortality after systemic fungal infection by driving lymphocyte dysfunction and systemic escape of commensal bacteria

Rebecca A Drummond, Jigar V Desai, Emily E Ricotta, Muthulekha Swamydas, Clay Deming, Sean Conlan, Mariam Quinones, Veronika Matei-Rascu, Lozan Sherif, David Lecky, Chyi-Chia R Lee, Nathaniel M Green, Nicholas Collins, Adrian M Zelazny, D Rebecca Prevots, David Bending, David Withers, Yasmine Belkaid, Julia A Segre, Michail S Lionakis

    Research output: Contribution to journalArticlepeer-review

    67 Downloads (Pure)

    Abstract

    Antibiotics are a modifiable iatrogenic risk factor for the most common human nosocomial fungal infection, invasive candidiasis, yet the underlying mechanisms remain elusive. We found that antibiotics enhanced the susceptibility to murine invasive candidiasis due to impaired lymphocyte-dependent IL-17A- and GM-CSF-mediated antifungal immunity within the gut. This led to non-inflammatory bacterial escape and systemic bacterial co-infection, which could be ameliorated by IL-17A or GM-CSF immunotherapy. Vancomycin alone similarly enhanced the susceptibility to invasive fungal infection and systemic bacterial co-infection. Mechanistically, vancomycin reduced the frequency of gut Th17 cells associated with impaired proliferation and RORγt expression. Vancomycin's effects on Th17 cells were indirect, manifesting only in vivo in the presence of dysbiosis. In humans, antibiotics were associated with an increased risk of invasive candidiasis and death after invasive candidiasis. Our work highlights the importance of antibiotic stewardship in protecting vulnerable patients from life-threatening infections and provides mechanistic insights into a controllable iatrogenic risk factor for invasive candidiasis.

    Original languageEnglish
    Pages (from-to)1020-1033.e6
    JournalCell Host & Microbe
    Volume30
    Issue number7
    Early online date13 May 2022
    DOIs
    Publication statusE-pub ahead of print - 13 May 2022

    Keywords

    • GM-CSF
    • IL-17A
    • antibiotics
    • invasive candidiasis
    • lymphocytes
    • trans-kingdom infections
    • vancomycin

    ASJC Scopus subject areas

    • Parasitology
    • Microbiology
    • Virology

    Fingerprint

    Dive into the research topics of 'Long-term antibiotic exposure promotes mortality after systemic fungal infection by driving lymphocyte dysfunction and systemic escape of commensal bacteria'. Together they form a unique fingerprint.

    Cite this