Cellular Responses to Flavivirus Infections: Stress Signaling at the Crossroads of Host Defense and Virus Infection

Flaviviruses, encompassing notable pathogens, like Dengue, Zika, West Nile, and tick-borne encephalitis viruses, elicit complex cellular stress responses, involving pathways such as the unfolded protein response (UPR), integrated stress response (ISR), apoptosis, autophagy, and the antiviral immune response. These pathways regulate cell fate by either promoting survival to counteract virus-induced damage or triggering cell death programs under prolonged and irreparable stress. Therefore, the primary aim of flavivirus-induced cellular responses is to protect cells and hinder viral propagation. Despite cellular defenses, flaviviruses have evolved various subversion strategies, mainly involving viral proteins, which enable successful infections even when cellular responses are activated. While these cellular pathways were previously perceived as separate entities, recent studies suggest interplay and dynamic shifts among these stress response pathways, underscoring the need for further investigation in this area. In this review, we explore the key pathways activated during flavivirus infections, examine mechanisms of viral subversion, and delve into the synergy of these pathways, thereby elucidating the impact on the progression of infection. A deeper understanding of these interactions will guide future efforts to define how cellular stress responses shape flavivirus infection and leverage this knowledge toward the development of targeted antiviral strategies.