Bile Acids Mediate Control of Acute Viral Infections Through Epigenetic Enhancement of Antiviral and Trained Immunity

Authors:
  • SFSlim Fourati
    Slim Fourati
  • JAJoao Lucas Lima Calandrini de Azevedo
    Joao Lucas Lima Calandrini de Azevedo
  • ESEileen Serrano
    Eileen Serrano
  • ASAna Carolina Santana
    Ana Carolina Santana
  • AEAnouk van Den Elzen
    Anouk van Den Elzen
  • YYYavor Yordanov
    Yavor Yordanov
  • INImpacc Network
    Impacc Network
  • RBRobert Balderas
    Robert Balderas
  • JDJoann Diray-Arce
    Joann Diray-Arce
  • GMGrace A. McComsey
    Grace A. McComsey
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Abstract
Bile acids (BAs) a complex family of immunometabolites can shape myeloid cell function; their role in antiviral immunity and clinical outcomes in human infection remains unclear. We identified an early plasma specific BA signature that distinguished moderate from severe COVID-19 trajectories (M vs. SCHP) in >1,100 hospitalized patients. Single-cell RNA and ATAC sequencing of PBMCs identified a TGR5⁺ monocyte subset in MCHP characterized by increased chromatin accessibility and expression of interferon-responsive antiviral and MHC class II pathways, and reduced IL-10 signaling. External datasets confirmed enrichment of this program in MCHP and healthy donors. In TGR5⁺ monocytes of MCHP, these BAs synergized with IFN-γ to enhance STAT1 activation, ERK/CREB1 signaling, and H3K27ac; independently promoting trained immunity recall responses. We reveal a previously unrecognized antiviral axis whereby these specific BAs activate TGR5 to drive transcriptional and epigenetic programs associated with upregulation of antiviral responses, trained immunity, and favorable clinical outcomes in COVID-19