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Published on: May 3, 2024
Oropouche virus infection induces pyroptosis in human THP-1 macrophages
Eduardo Jurado-Cobena1, Cigdem Alkan2, Tetsuro Ikegami3
1Department of Microbiology and Immunology, The University of Texas Medical Branch at Galveston, 301 University Boulevard, TX, Galveston, 77555, USA.
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.
Insights
Oropouche virus (OROV) infects macrophages, triggering NLRP3 inflammasome activation. This leads to pyroptosis and the release of IL-1β, a key inflammatory cytokine, contributing to Oropouche fever pathogenesis.
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Oropouche virus (OROV) causes Oropouche fever, an emerging zoonotic disease in the Americas.
- Severe OROV infections can lead to neurological and developmental complications.
- The role of macrophages and inflammasome pathways in OROV pathogenesis is not well understood.
Purpose of the Study:
- To investigate the role of the NLRP3 inflammasome in OROV-infected human macrophages.
- To determine if OROV infection induces pyroptosis and IL-1β release in macrophages.
Main Methods:
- Human THP-1 macrophages were infected with OROV.
- Analysis of inflammasome activation, caspase activity, pyroptosis markers (GSDMD, GSDME), and IL-1β release.
- Experiments were conducted using NLRP3-deficient macrophages.
Main Results:
- Macrophages, but not monocytes, are susceptible to OROV infection.
- OROV infection induced pyroptosis via caspase-1, -3, and -8 activation, leading to GSDMD/GSDME cleavage and IL-1β release.
- NLRP3 deficiency abrogated OROV-induced caspase activation, pyroptosis, and IL-1β production.
Conclusions:
- OROV infection activates the NLRP3 inflammasome in macrophages, driving pyroptosis and IL-1β release.
- This NLRP3-mediated pathway is crucial for OROV-induced inflammation and pathogenesis.
- Macrophages play a significant role in the host response to Oropouche fever.
