Saturday, May 24, 2025
5/24/2025
Defining mechanisms of chronic CHIKV disease in joint associated tissue - PROJECT SUMMARY This proposal aims to elucidate the mechanisms that drive the development of chronic chikungunya virus (CHIKV) arthritis (CCA). CHIKV is a mosquito-borne RNA alphavirus of global health concern. The acute phase lasts for 4-8 days and involves severe joint and muscle pain. In many patients, acute disease resolves without lasting symptoms; however, up to 50% of patients develop CCA characterized by incapacitating inflammatory musculoskeletal disease that persists for months to years. There are no approved therapeutics to treat CCA and the pathogenic mechanisms remain poorly understood. In preliminary studies using a mouse model of chronic CHIKV disease, I identified an increase in pro-inflammatory macrophages defined by elevated expression of NLRP3, TNF, and IL-1β, implicating macrophages as pathogenic effectors of chronic CHIKV disease. In addition, using scRNAseq and cell sorting approaches, I found that the persistent CHIKV RNA detected in joint-associated tissues is almost exclusively harbored in macrophages. Given that the NLRP3 inflammasome can be activated by viral RNA, these data offer a mechanism by which persistent viral RNA in macrophages promotes chronic inflammation. I also discovered that joint tissue CD4+ T cells during chronic CHIKV infection express elevated IFN-γ, suggesting a role for CD4+ T cells in the activation of macrophages. Finally, flow cytometric analysis revealed an increase in SLAMF7 on macrophages and CD4+ T cells during chronic disease. SLAMF7 contributes to TNF and IL-1β expression in macrophages and this is regulated by IFN-γ. Notably, in rheumatoid arthritis, macrophages are pathogenic due to elevated expression of SLAMF7 and inflammatory genes including IL-1β, TNF, and IL-6 that promote cartilage and bone destruction. These findings suggest macrophages share a similar pathogenic role in CCA. I hypothesize that CHIKV RNA persists in macrophages and induces inflammasome- mediated pro-inflammatory programming. In addition, SLAMF7 and CD4+ T cell interactions contribute to macrophage mediated CCA. My proposed studies will (i) define a viral reservoir in macrophages in joint associated tissue, (ii) assess mechanisms that drive pro-inflammatory programming in macrophages, (iii) elucidate the role of CD4+ T cells in regulating pro-inflammatory macrophages, (iv) identify the contribution of SLAMF7 in CHIKV infection, and (v) provide insight on the consequence of pro-inflammatory macrophages in CCA. The knowledge gained from these studies will help identify potential therapeutic targets to mitigate chronic CHIKV disease.
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