Identifier

etd-10192016-115334

Degree

Doctor of Philosophy (PhD)

Department

Veterinary Medical Sciences - Pathobiological Sciences

Document Type

Dissertation

Abstract

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that circulates predominantly in tropical and subtropical regions. Infection results in severe debilitating polyarthralgia during the acute phase of disease, and reports suggest that chronic arthralgia lasting months to years after the initial infection can occur. More severe and prolonged disease has been associated with pre-existing joint disease, though this has not been experimentally examined. In the research presented herein, two established mouse models (adult IRF 3/7 -/- -/- and wild-type C57BL/6J mice) were utilized to characterize CHIKV-associated bone and joint disease and evaluate its impact on the progression of pre-existing osteoarthritis (OA) utilizing histopathology, μCT, and serology. During acute stages of the disease, CHIKV infection resulted in synovitis, cartilage necrosis, and periosteal necrosis or periostitis. Additionally, IRF mice had severe ischemic bone marrow necrosis, and C57BL/6J mice developed periosteal new bone proliferation. During chronic stages of disease (90 DPI), there was ongoing and progressive synovitis, tendonitis, enthesitis, and cartilage damage, though periostitis and periosteal bone proliferation had resolved. Infection with CHIKV in mice with pre-existing OA had no significant impact on total synovitis scores or chondrocyte cell death, but caused a decrease in volume of osteophytes and subchondral bone, as compared to OA alone. Serology results in both the footpad and intra-articular C57BL/6J models indicated there were alterations in RANKL and OPG associated with CHIKV infection, demonstrating potential changes in bone dynamics. The current experiments demonstrated novel lesions of CHIKV-associated bone and joint disease that have important ramifications for the treatment and prevention of disease. Periosteal bone proliferation associated with CHIKV is a potentially painful but reversible process, whereas articular cartilage damage is progressive and represents a potential mechanism for chronic CHIKV-associated joint disease. Additionally, the alterations in bone associated with CHIKV infection and pre-existing OA, in conjunction with changes in the RANKL-OPG pathways, could have significance in clinical monitoring of OA and treatment choices in individuals with concurrent diseases. Future studies would help determine if RANKL and OPG levels could be useful for tracking disease progression in people and establish the long-term effects of CHIKV infection on OA progression.

Date

2016

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Mores, Christopher N

DOI

10.31390/gradschool_dissertations.4273

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