Two orthobunyaviruses: OYAV and EBIV co-opt the AhR-CYP1A1 axis to suppress type I interferon responses.

Abstract

The type I interferon (IFN-I) system serves as a frontline defense against viral infection, yet how orthobunyaviruses counteract this pathway remains poorly defined. Here, we identify cytochrome P450 1A1 (CYP1A1) as a crucial host factor promoting infection by two emerging orthobunyaviruses-Oya virus (OYAV) and Ebinur Lake virus (EBIV). Transcriptomic and functional analyses demonstrate that CYP1A1 overexpression enhances viral RNA synthesis, whereas its CRISPR-Cas9-mediated knockout attenuates infection. Mechanistically, OYAV and EBIV activate the aryl hydrocarbon receptor (AhR), driving its nuclear translocation and subsequent upregulation of CYP1A1. Deficiency of CYP1A1 potentiates IFN-β production and interferon-stimulated gene (ISG) expression, while its overexpression suppressed antiviral signaling, revealing an immunomodulatory role that is distinct from its canonical metabolic function. Collectively, this work defines the AhR-CYP1A1 axis as a conserved immune-evasion module exploited by emerging orthobunyaviruses and highlights the innate immune pathway as a potential therapeutic target against these emerging threats.