Revealing Distinct Host Responses through Transcriptomic Analysis of Susceptible and Non-Susceptible Cells Infected with Fowl Adenovirus Serotype 4 (Chicken hepatoma cell lines and chicken embryonic fibroblasts)

Fowl adenovirus serotype 4 (FAdV-4) infections result in major economic losses in the poultry industry. However, the virus-host interactions underlying FAdV-4 pathogenesis remain unclear, including differences in susceptible versus non-susceptible cells. We performed transcriptomic analysis of FAdV-4 infected leghorn male hepatocellular (LMH) and chicken embryo fibroblast (CEF) cells to uncover cell-specific host responses. Although FAdV-4 replicated more efficiently in LMH cells, it provoked limited interferon-stimulated gene induction. In contrast, FAdV-4 infection triggered robust antiviral responses in CEF cells, including upregulation of cytosolic DNA sensing and interferon-stimulated genes. Knockdown of key cytosolic DNA sensing molecules enhanced FAdV-4 replication in LMH cells while reducing interferon-stimulated gene expression. Our study demonstrates that FAdV-4 provokes differential host responses in cancerous and non-cancerous cells, which may underlie tissue tropism. Cytosolic DNA sensing appears to mediate antiviral innate immunity against FAdV-4.