Chronic Joint Disease Caused by Persistent Chikungunya Virus Infection Is Controlled by the Adaptive Immune Response

Abstract

f Chikungunya virus (CHIKV) is a reemerging mosquito-borne pathogen that causes incapacitating disease in humans characterized by intense joint pain that can persist for weeks, months, or even years. Although there is some evidence of persistent CHIKV infection in humans suffering from chronic rheumatologic disease symptoms, little is known about chronic disease pathogenesis, and no specific therapies exist for acute or chronic CHIKV disease. To investigate mechanisms of chronic CHIKV-induced disease, we utilized a mouse model and defined the duration of CHIKV infection in tissues and the associated histopathological changes. Although CHIKV RNA was readily detectable in a variety of tissues very early after infection, CHIKV RNA persisted specifically in joint-associated tissues for at least 16 weeks. Inoculation of Rag1 ؊/؊ mice, which lack T and B cells, resulted in higher viral levels in a variety of tissues, suggesting that adaptive immunity controls the tissue specificity and persistence of CHIKV infection. The presence of CHIKV RNA in tissues of wild-type and Rag1 ؊/؊ mice was associated with histopathological evidence of synovitis, arthritis, and tendonitis; thus, CHIKV-induced persistent arthritis is not mediated primarily by adaptive immune responses. Finally, we show that prophylactic administration of CHIKV-specific monoclonal antibodies prevented the establishment of CHIKV persistence, whereas therapeutic administration had tissue-specific efficacy. These findings suggest that chronic musculoskeletal tissue pathology is caused by persistent CHIKV infection and controlled by adaptive immune responses. Our results have significant implications for the development of strategies to mitigate the disease burden associated with CHIKV infection in humans.

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies

“…Development of CHIKV-neutralizing antibodies is essential to control CHIKV viremia (125,137,147,150,151). CHIKVinfected humans, mice, and NHPs develop potent and neutralizing IgM and IgG antibodies that control viremia and confer cross-protection against secondary CHIKV infections in animal models (125,137,143,147,(150)(151)(152).…”

“…CHIKVinfected humans, mice, and NHPs develop potent and neutralizing IgM and IgG antibodies that control viremia and confer cross-protection against secondary CHIKV infections in animal models (125,137,143,147,(150)(151)(152). In humans, IgM levels are detected within 5-7 days after the onset of symptoms (153), peak several weeks after infection (154), and begin to wane over the next several months (154).…”

Recent progress on chikungunya virus research

“…In acute phase of post-infected WT mice, viremia occurs and lasts for 4 days, followed by arthritis appearing in day 6-8 (Gardner et al, 2010). In chronic phase, persistent synovitis exists at least for 84 days (Hawman et al, 2013). named capsid, E3, E2, 6K/TF, and E1 proteins, comprised of 261, 64, 423, 61, and 435 amino acids, respectively.…”

“…The exact function of T cells during CHIKV infection depends on the balance between various T cell subsets. WT mice infected with CHIKV strain SL15649 have more severe tissue pathology than Rag1 -/-mice in acute phase, suggesting a potentially pathogenic role for T cells and/or B cells (Hawman et al, 2013). Therapy with CTLA4-Ig can alleviate acute joint swelling in mice as it can reduce T cell accumulation in the tissues, providing another piece of evidence in support of the pathogenic role of T cells (Jonathan et al, 2017).…”

Chikungunya and Its Interaction With the Host Cell

“…Disease signs and symptoms following infection with CHIKV have been associated with CHIKV infection of cells in musculoskeletal tissues, such as fibroblasts and osteoblasts, and infiltration of inflammatory cells-consisting predominantly of monocytes, macrophages, natural killer cells, and T cells-in musculoskeletal tissues. Recent works have demonstrated that mice lacking mature T and B cells and mice lacking CD4 + T cells had reduced joint swelling and less severe musculoskeletal tissue injury during the acute stage of CHIKV disease, suggesting a pathogenic role for CD4 + T cells in CHIKV disease [80,81].…”