Repurposing eravacycline as an immunomodulator for immunodeficiencies driven by anti-IFN-γ autoantibodies.

INTRODUCTION

Adult-onset immunodeficiency (AOID) driven by pathogenic anti-interferon-γ (IFN-γ) autoantibodies (AIGA) mimics inborn errors of IFN-γ signaling, causing life-threatening nontuberculous mycobacterial and fungal infections. Current B-cell depletion or prolonged antimicrobials fail to directly reverse autoantibody-mediated IFN-γ blockade. We hypothesized that small molecules binding AIGA-targeted IFN-γ epitopes could sterically disrupt pathogenic autoantibody-cytokine complexes and restore JAK-STAT1 signaling.

METHODS

We conducted structure-based high-throughput virtual screening of an FDA-approved drug library using the IFN-γ/IFNGR1 crystal structure (PDB: 1FG9). Compounds predicted to bind AIGA-targeted IFN-γ epitopes were selected for functional testing for their ability to restore IFN-γ signaling inhibited by patient plasma containing AIGA. Patients were stratified into drug-free remission or non-remission groups for comparative analyses.

RESULTS

Eravacycline, a tetracycline antibiotic, was identified as a lead candidate with high predicted affinity (-9.1 kcal/mol) for AIGA-targeted IFN-γ epitopes. In functional assays, eravacycline dose-dependently restored IFN-γ-induced STAT1 phosphorylation inhibited by AIGA, outperforming tigecycline under the same conditions (p < 0.001), and partially reversed AIGA-mediated suppression of CXCL9 (p < 0.01) and TNF-α (p < 0.001) expression. These effects were observed in both drug-free remission and non-remission groups.

CONCLUSIONS

Eravacycline is the first tetracycline shown to break pathogenic autoantibody-cytokine protein-protein interactions in human disease, restoring Th1 immunity ex vivo. These findings establish proof-of-concept for structure-guided reversal of anti-cytokine autoantibody pathogenicity using an FDA-approved antimicrobial, offering a rapidly translatable dual-action therapy for AIGA-driven AOID and potentially other anti-cytokine autoantibody syndromes.