Oropouche virus infection induces pyroptosis in human THP-1 macrophages

Abstract

Oropouche fever, an emerging zoonotic viral disease in Central and South America, is caused by Oropouche virus (OROV). While typically self-limiting, severe complications such as aseptic meningoencephalitis, miscarriage, and neonatal malformations can occur. Macrophages are critical in host defense, but the pathological mechanisms underlying OROV infection remain unclear. IL-1β, a key pro-inflammatory cytokine, plays a central role in the febrile response and is regulated by inflammasomes, such as NLRP3. This study investigates NLRP3-mediated IL-1β maturation and pyroptotic cell death in OROV-infected human THP-1 macrophages. Our findings reveal that macrophages, but not monocytes, are permissive to OROV infection and undergo pyroptosis through the activation of caspases-1, -3, and -8, resulting in the cleavage of GSDMD and GSDME, and the release of IL-1β. Interestingly, the cleaved form of GSDMD was predominantly the inactive p23 fragment. Furthermore, NLRP3-deficient macrophages failed to activate caspases, cleave Gasdermins, or produce IL-1β upon infection. These results demonstrate that OROV infection triggers NLRP3-mediated IL-1β maturation and release via pyroptosis in macrophages, underscoring their potential role in OROV pathogenesis.