Understanding immunobiology of chikungunya virus disease using mouse models

Abstract

Chikungunya virus (CHIKV) is a mosquito borne alphavirus, whose primary disease manifestation in humans is acute and chronic, often debilitating polyarthritis/polyathralgia. Current treatments are often inadequate. This thesis aims to elucidate the roles of several immune components in CHIKV disease, using a mouse model of CHIKV infection and disease, which recapitulates many aspects of human disease. An improved understanding of the immunobiology of CHIKV is required for future development of new interventions for this recently re-emergent virus.CHIKV polyarthritis/polyathralgia is associated with a prolific monocytes/macrophage infiltration of musculoskeletal tissue in humans, monkeys and mice. The infection in all species is associated with high levels of chemokine (C-C motif) ligand 2 (CCL2), a chemokine that binds chemokine (C-C motif) receptor 2 (CCR2) and is involved in recruitment of monocytes to the sites of infection. Targeting CCL2 or CCR2 signalling has thus been proposed as a potential treatment option for CHIKV disease. Results herein show that CHIKV infection of mice deficient in CCR2 led to a significantly more pronounced and prolonged arthritis that was associated with cartilage (iii) many of the inflammatory pathways identified in chronically infected mouse feet were also found in chronic CHIKV patients. These observations suggest that chronic disease is due to ongoing inflammation stimulated by persistently replicating viral RNA and viral proteins encoded by that RNA (Chapter 5).In conclusion, this thesis has shown, that inflammatory CCR2+ monocyte can be critical for preventing excessive pathology and resolving inflammation, that distinct immune factors control CHIKV viraemia and arthritis, and that long-term persistence of replicating CHIKV RNA might be the cause of protracted arthritic manifestations in CHIKV patients. These studies will hopefully inform future development of intervention for CHIKV.III