Comparative Analysis of Innate Immune Modulation Between BeAn19991 and ISCDC-2024 Oropouche Virus Strains

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 associated with the expansion of 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 incompletely 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), focusing on innate immune response. We examined the sensitivity of the two strains to IFN-β antiviral activity and their ability to induce type I IFN in fibroblast. Furthermore, we characterized the innate immune response triggered by in-vitro infection of PBMCs from healthy donors. Although the two viral strains exhibited a similar plateau in viral RNA accumulation and comparable sensitivity to exogenous IFN-β, the IFN-β induction in fibroblasts was delayed, with higher levels induced by ISCDC-2024 than by BeAn19991. Moreover, the two strains displayed distinct innate immune profiles in PBMCs: BeAn19991 predominantly induced a robust antiviral IFN-driven response, whereas ISCDC-2024 infection was associated with an IL-6-dominated inflammatory pattern. Overall, these findings highlight distinct phenotypic features of the contemporary reassortant isolate and suggest strain-specific differences in the modulation of innate immunity, potentially reflecting distinct immune evasion strategies. If confirmed, this hypothesis 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.