Chikungunya Virus (CHIKV) Pathogenesis: From Acute Fever to Chronic Arthritis-Immune Mechanisms and Therapeutic...

Chikungunya Virus (CHIKV) is an arthropod-borne alphavirus that represents a substantial worldwide health burden. A percentage of patients go on to suffer from Chronic Chikungunya Arthritis (CCA) that lasts for months, or even years, and causes disability. The immunopathogenic processes that mediate the evolution from acute febrile illness to chronic arthritis are complicated and not well elucidated. The present review will attempt to comprehensively describe the immunological shifts associated with CHIKV infection, addressing the impact of viral persistence, autoimmunisation, and uncontrolled cytokine cascades on CCA pathogenesis. It also pursues the synthesis of the consequences of these mechanisms for designing new therapeutic approaches. A systematic search in the English literature, including PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar, was performed from January 2000 to August 2024. Immunopathogenesis of CHIKV and experimental therapeutics in humans, animal models, and in vitro systems were considered. Results: Data were extracted and summarized narratively to bring out key themes. It appears that persistent virus, especially its RNA remnants in the form of viral antigen within synovial tissues and myeloid cells, plays a role in further chronic inflammation through prolonged activation of innate immunity. Autoimmunity mediated by molecular mimicry (e.g., anti-Ephrin-B2 antibodies) and disruptions of the cytokine network, with sustained high levels of IL-6, IL1β, and TNF-α, are important for the CCA pathogenesis. Lessons learned through the use of humanized mice focus on the contribution of CD4+ T cells and activation of synovial fibroblasts. Treatment approaches include combination antiviral-immunomodulatory regimens (remdesivir with tocilizumab), B-cell depletion, and cytokine blockade. The development of CCA may be mediated by a complex interaction between viral persistence and host immunopathology. Intervention at these pathways through combined antiviral and immunomodulatory strategies promises an appealing approach to halt chronic disease and enhance patient outcomes.