STING-mediated antiviral response: insights into MVA replication control in avian cells

The safety-tested Modified Vaccinia virus Ankara (MVA) is a well-characterized mutant virus widely used in fundamental research to elucidate the functions of Poxvirus host-interaction factors. Beyond its safety profile, MVA is an attractive viral vector for vaccine development due to its genetic stability and ability to efficiently infect antigen-presenting cells, such as dendritic cells and tumor cells. In this report, we investigated the interplay between MVA and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) antiviral pathway in chicken fibroblast cell lines (wild-type DF-1 and knock-out STING) to verify whether manipulation of the STING axis could impact MVA replication and cell responses. Our findings demonstrate that STING-mediated signaling plays a role in contrasting the replication of MVA. Upon MVA infection, the loss of STING hampered the expression of type I interferons (IFNs) and, in turn, interferon-stimulated gene 15 (ISG15) and interferon-induced transmembrane protein 3 (IFITM3). In line with these results, the expression of early and late MVA genes was enhanced, and DNA replication occurred earlier and was more abundant. Interferon regulatory factor 1 (IRF1) and myeloid differentiation primary response 88 (MyD88) were significantly induced by MVA infection in STING-KO cells, indicating that their responses to MVA infection are independent of the cGAS/STING axis. Collectively, these results refine our knowledge of MVA-host interaction in chicken fibroblasts and offer insights to guide strategies for enhancing Poxvirus vaccine vector production.IMPORTANCEGiven the context-dependent nature of STING antiviral activity, it is critical to broaden the investigation in order to clarify the virus-host response mechanisms across different species, particularly in chicken fibroblasts, to provide insights into MVA-based vaccine production improvements.