Comparative analysis of Innate Immune modulation among BeAn19991 and 2023–2025 Emerging Oropouche Virus

Oropouche virus (OROV) has re-emerged as a significant public health threat during the 2023–2025 outbreak, characterized by an unprecedented geographic expansion beyond endemic regions. The virus has been detected in various regions including the Caribbean, as well as in Europe and the United States, among travelers from Central and South America. This epidemic was driven by a novel reassortant strain, which may exhibit enhanced viral fitness and immune evasion properties. Although orthobunyaviruses are known to counteract interferon responses, the specific strategy adopted by OROV remains poorly understood. In this study, we compared the in vitro behavior of the prototype strain BeAn19991 and a 2024 isolate representing the reassortant virus responsible for the 2023–2025 epidemic (ISCDC-2024), in the context of the innate immune response. We examined both the sensitivity of the two strains to IFN-β antiviral activity and their ability to induce type I IFN. Furthermore, we characterized the innate immune response triggered by in vitro infection of PBMCs from healthy donors. Although the two viral strains exhibit similar replication kinetics, they seem to display markedly distinct interactions with the host innate immune response system: BeAn19991 predominantly induced a robust antiviral IFN-driven response, whereas ISCDC-2024 infection was associated with a wider pro-inflammatory profile, coupled with higher sensitivity to exogenous IFN-β. Overall, these findings reveal strain-specific differences in the modulation of innate immunity, likely reflecting distinct immune evasion strategies. These differences could have significant implications for infection transmission, viral persistence and disease severity, highlighting the need for continuous surveillance and functional characterization of emerging OROV strains to drive public health interventions and antiviral countermeasures.