Exosome-mediated transfer of bta-miR-2484 upregulates JAK-STAT pathway to inhibit BoHV-1 replication by targeting SOCS5

Abstract Bovine herpesvirus-1 (BoHV-1)-induced infectious bovine rhinotracheitis has had a considerable economic impact on the global cattle industry. Exosomes have recently attracted significant interest in the field of viral infections, primarily due to their capacity to facilitate the transfer of genetic material between cells. MicroRNAs (miRNAs) have been demonstrated to play a crucial role in virus–host interactions, given their status as the most abundant nucleic acid in exosomes. However, existing research on the relationship between host cell exosomes and their miRNAs and BoHV-1 replication remains limited. The present study revealed that BoHV-1 infection leads to increased exosome release, and that exosomes released from BoHV-1-infected MDBK (Madin-Darby bovine kidney) cells inhibit BoHV-1 proliferation. Furthermore, we found that BoHV-1 infection resulted in changes to the expression profile of miRNAs within exosomes. The miRNA bta-miR-2484 is one of the differentially expressed miRNAs that is significantly upregulated and targets suppressor of cytokine signaling 5 (SOCS5), leading to its downregulation. This activates the JAK-STAT pathway and promotes the expression of interferon-stimulated genes (ISG15, OAS1), boosting the antiviral response against BoHV-1. Together, these results show that BoHV-1 infection leads to the selective enrichment of bta-miR-2484 in exosomes, which then inhibit viral replication by priming JAK-STAT antiviral signaling via SOCS5. This study provides novel insights into the immunoregulatory function of exosomal miRNAs during BoHV-1 infection and highlights exosomal bta-miR-2484 as a potential therapeutic target for controlling BoHV-1-associated disease.