Emerging threat of Oropouche virus: Clinical features, experimental models, and virulence.

Oropouche fever, caused by Oropouche virus (OROV) and transmitted primarily by Culicoides midges, has historically been considered a neglected tropical disease characterized by an acute, self-limiting febrile illness and occasional meningoencephalitis, mostly within or along the Amazon rainforest. However, the explosive 2023-2025 outbreak expanded well beyond the Amazon region, including into the Caribbean, and was associated with a broader clinical spectrum encompassing meningoencephalitis, Guillain - Barré syndrome, persistent viral infection, lethal hemorrhagic fever, fetal loss, and neonatal abnormalities. Experimental animal models of OROV infection are available; however, substantial variation in host susceptibility across species complicates the interpretation of pathogenic mechanisms. The major virulence factor, the NSs protein, mediates inhibition of host cellular transcription, whereas the biological functions of the NSm protein remain largely unknown. This review outlines current knowledge on OROV outbreaks, clinical features, animal models, and virulence determinants, underscoring major knowledge gaps in understanding OROV virulence and pathogenesis.