A storm is born: immune activation and pathogenesis in arthritogenic alphavirus infections

Arthritogenic alphaviruses, including chikungunya (CHIKV), Ross River, and Mayaro viruses, are emerging global viruses responsible for causing arthralgia and chronic arthritis. Following mosquito-borne transmission, they quickly initiate infection in the skin, including in resident immune cells, and disseminate systemically into musculoskeletal tissues. The innate immune system responds rapidly through the activation of interferons, the production of inflammatory cytokines, and the recruitment of monocytes, macrophages, neutrophils, and dendritic cells, while the adaptive immune response, particularly virus-specific T and B cells, is critical for viral clearance. However, excessive immune activation can lead to both acute and chronic musculoskeletal pain through cytokine storm, tissue damage, and supporting immunopathology. Additionally, viral persistence and immune evasion may contribute to the development of chronic synovitis and cartilage degradation, leading to persistent joint pain. Despite recent advances, antiviral treatments remain unavailable, and to date, there is only one vaccine licensed (VIMKUNYA™ in 2025, against CHIKV), underscoring the urgent need for further research. This review explores the complex interplay between host immune responses and viral factors that lead from acute infection to chronic inflammation. Furthermore, it highlights key gaps in understanding viral persistence and immune evasion, and how to predict chronic diseases to improve therapeutic and preventive strategies against arthritogenic alphaviruses.