Determinants of orthoflavivirus tropism in humans: from cellular entry to organ-specific pathogenesis

Orthoflaviviruses, including dengue virus, tick-borne encephalitis virus, West Nile virus, Zika virus, Japanese encephalitis virus, and yellow fever virus, cause a wide spectrum of diseases in humans despite sharing a similar genomic organization. These viruses pose a growing global threat as they are spreading widely, treatment options remain limited, and both climate change and expanding mosquito populations increase the risk of outbreaks worldwide. This review summarizes the determinants of their human tropism, the capacity to infect specific cell types, tissues, and organs. We synthesized current knowledge on how viral factors, including host factor utilization and immune cell trafficking, shape tropism across multiple layers. Central to this process are sequential host barriers that govern infection, including viral attachment, internalization, and replication. Understanding these determinants is essential for informing strategies to mitigate the global burden of these medically important pathogens.