Investigation of immune mechanisms driving the pathogenesis of chronic chikungunya virus disease 2254154

Abstract Introduction Arthritogenic alphaviruses such as chikungunya virus (CHIKV) cause chronic inflammatory arthritis affecting thousands globally, yet there are no effective targeted therapies. Persistent joint inflammation despite viral clearance suggests a critical role for virus-specific, immune-mediated mechanisms. However, immune mechanisms underlying the development of chronic arthritic disease post chikungunya infection is currently unknown. Recent work suggests a pathogenic role for TNF+-producing CHIKV-specific CD4+ T cells in chronic disease and macrophages as the primary target of CHIKV infection. Therefore, it is essential to uncover the molecular crosstalk between different immune cell subsets and define their contribution to disease pathogenesis in humans. Methods Using high resolution spectral flow cytometry and in vitro co-cultures, we dissected the phenotype and function of diverse immune cell populations, including monocytes, dendritic cells, NK cells and T cells in PBMCs from CHIKV-infected individuals with chronic chikungunya disease compared to those who recovered post-infection. Results We identified the functional profile of circulating monocytes, dendritic cells and NK cells in individuals with chronic chikungunya disease and identify the key cytokines and molecules that are released by these immune cell subsets as a result of T cell activation. Additionally, we observe a high production of TNF+, IL-10 and GM-CSF and a lower expression of HLA-DR in monocytes, indicating a pro-inflammatory profile that is exclusive to individuals with chronic disease. This will allow us to understand how monocyte activation affects T cell differentiation and function. Conclusion Here, we identify the key cytokines and molecular players that mediate immune crosstalk and allow differentiation of CD4+ T cells into pro-inflammatory cells. This work will uncover immune mechanisms that drive alphavirus-mediated chronic arthritic diseases. Funding Source n/a Topic Categories Viral Immunology (VIR)