Exploring Chronic Disease and Sex Bias in Chikungunya Virus
Open Access DepositedChikungunya virus (CHIKV) is an arthritogenic alphavirus that causes acute febrile illness followed by persistent joint pain in a substantial proportion of patients. Many individuals experience chronic, relapsing-remitting arthritis months to years after initial infection, yet the mechanisms that drive long-term disease remain unclear. This dissertation investigates immunologic factors contributing to chronic CHIKV arthritis using a post-CHIKV arthritis mouse model, with an emphasis on IL2-mediated T cell regulation, single-cell RNA sequencing (scRNA-seq) of the tarsal joint microenvironment, and sex-based differences in host immune responses.To evaluate potential therapeutic strategies, IL2-based treatments, including recombinant IL2, an anti-IL2 monoclonal antibody (mAb), and an IL2/anti-IL2 mAb complex, were administered after viral clearance. The IL2 antibody increased regulatory T cell (Treg) activation with only a modest increase in effector T cells (Teff), corresponding with reduced joint inflammation. In contrast, recombinant IL2 alone did not expand or activate Tregs, and the IL2/anti-IL2 complex increased both Treg and Teff activity, contributing to worsened disease. Histologic evaluation confirmed synovitis as an early and consistent feature of post-CHIKV disease, often accompanied by periostitis and myositis. To further characterize the chronic joint environment, scRNA-seq was performed on tarsal joint cells from infected and uninfected mice at 21 days post-infection. Thirteen distinct cellular clusters were identified, with macrophages and neutrophils comprising the largest populations. Apparent differences in cell abundance and gene expression were also observed between male and female mice. These sex-specific patterns were also reflected in RT-qPCR analyses during acute infection, in which males showed substantially higher fold changes in a subset of inflammatory genes. Findings from this dissertation demonstrate that IL2-based therapies can affect Tregs and Teff cells and alter disease severity, that the tarsal joint microenvironment in chronic disease contains diverse immune cell populations, that the individual responses to acute infection and chronic disease can vary among mice, and that sex is a significant determinant of both acute and chronic immune responses. Together, these studies contribute to a deeper understanding of chronic post-CHIKV arthritis and identify several potential pathways for future therapeutic and biomarker development.
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