Bovine viral diarrhea virus suppresses type I IFN production by inducing MAVS degradation via autophagy mediated by the ROS-endoplasmic reticulum stress axis

Abstract

ABSTRACT Bovine viral diarrhea virus (BVDV) is a major animal pathogen with a broad host range, causing gastrointestinal, respiratory, and reproductive diseases in cattle worldwide. BVDV exists as two biotypes: cytopathic (cp) and non-cytopathic (ncp). Although both cpBVDV and ncpBVDV have developed sophisticated strategies to evade or subvert host antiviral innate immune response, the underlying mechanisms remain incompletely understood. Autophagy, a process essential for maintaining cellular homeostasis, plays an important role in regulating viral replication and antiviral immunity. In this study, we demonstrated that the induction of autophagy with rapamycin enhanced the production of infectious progeny for both cpBVDV and ncpBVDV, whereas pharmacological inhibition of autophagy with 3-MA reduced viral yields. We further showed that modulating autophagy significantly influenced the early stages of the viral life cycle and the production of type I IFN (IFN-I). Notably, overexpression of BECN1 suppressed the synthesis of IFN-α and IFN-β, thereby promoting the replication of both cpBVDV and ncpBVDV. Conversely, RNA interference-mediated knockdown of BECN1 potentiated the antiviral innate immune response and restricted viral replication. Mechanistically, BECN1 was found to inhibit RIG-I–MAVS pathway activation by promoting ubiquitination and subsequent degradation of mitochondrial antiviral signaling (MAVS) protein, leading to suppression of IFN-I production. Additionally, both cpBVDV and ncpBVDV were shown to induce autophagy via the ROS-endoplasmic reticulum stress axis. These findings deepen our understanding of how BVDV evades host immunity and may inform the development of preventive strategies against BVDV infection. IMPORTANCE Bovine viral diarrhea virus (BVDV), the causative agent of bovine viral diarrhea-mucosal disease, is a major global threat to cattle health. BVDV employs sophisticated strategies to evade host defense and facilitate its replication. Understanding these mechanisms is crucial for developing effective vaccines and antiviral agents. Our study elucidates how cytopathic BVDV and non-cytopathic BVDV subvert the host’s antiviral innate immune response by exploiting autophagy to inhibit the RIG-I–MAVS pathway. A key finding is that BECN1-mediated autophagy directly targets MAVS protein for degradation via a specific BECN1 and MAVS interaction. Furthermore, we demonstrate that BVDV activates autophagy through ROS-ER stress axis to promote its replication. These insights reveal a novel immune evasion mechanism of BVDV and highlight the therapeutic potential of autophagy inhibition in treating BVDV-related diseases.

Affiliated Institutions

• Fudan University CN
• Northeast Agricultural University CN
• Zhejiang A & F University CN
• Zhongkai University of Agriculture and Engineering CN

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