The BTK-DDX41 axis of the STING pathway is activated during cytomegalovirus lytic infection

Human cytomegalovirus (CMV) is an ubiquitous pathogen that poses a significant threat to immunocompromised individuals, highlighting the critical role of innate immunity in controlling this viral infection. Despite extensive research, the complex mechanisms underlying innate immunity against CMV and the virus's strategies for evading immune detection remain only partially understood. This study identifies the activation of the cellular BTK-DDX41-STING innate signaling axis during lytic CMV infection, which ultimately results in protective interferon responses. Our findings show that CMV infection triggers the cytoplasmic redistribution of the cellular protein, DDX41, leading to reduced phosphorylation and activity, thereby undermining its protective function. Additionally, pharmacological inhibition of BTK enhances viral protein expression and replication, highlighting the importance of this pathway in immune defense. Our work identifies BTK- and DDX41-dependent STING signaling as important for innate immune responses against CMV and further advances understanding of CMV's manipulation of these responses.