Bridging two hosts: how intracellular environments shape flaviviral infection

Mosquito-borne flaviviruses replicate in physiologically and biochemically distinct host environments in humans and mosquitoes, providing a unique window into conserved and host-specific mechanisms shaping viral infection efficiencies and outcomes. This review focuses specifically on intracellular factors, including proteins, metabolites, innate immune effectors, and stress sensors in human and mosquito cells that collectively regulate the flaviviral life cycle and host cell survival, with specific emphasis on dengue virus. We discuss both conserved dependencies and species-specific differences in receptor usage, membrane remodeling, RNA translation, and replication strategies that influence viral dynamics across hosts. We further highlight how host metabolism, innate immune sensing, and stress response pathways drive divergent outcomes in virus-infected cells. In mammalian cells, rapid viral replication activates interferon-mediated antiviral responses that limit viral infection, but also lead to cytopathic effects and apoptosis. In contrast, mosquito cells support persistent, non-cytopathic infection mediated by RNA interference-dependent control of viral replication, coupled with antioxidant and anti-apoptotic defenses that maintain cellular homeostasis. This comparative perspective integrates insights from mammalian and mosquito systems to illustrate how host environments shape flaviviral infection, host susceptibility, and infection outcomes. Identifying these intracellular determinants of infection and persistence will be critical for defining host susceptibility, understanding barriers to cross-species transmission, and predicting viral emergence potential.