Chikungunya (CHIK) is an emerging viral disease, which causes significant morbidity and mortality throughout tropical/subtropical areas of the world, including a recent outbreak in the Americas. Disease typically includes fever, rash, and arthritis. Joint involvement is generally self-limiting, but infection with Chikungunya virus (CHIKV) can lead to chronic debilitating arthritis that can last for months to years. With no vaccine and no licensed treatment, suitable animal models of CHIKV are needed to test intervention strategies. We developed a model of CHIK in DBA1/J mice that develop joint swelling, increase in inflammatory cytokines and splenomegaly in mice, which include important symptoms of disease seen in infected humans. We used this model to test the hypothesis that treatment with immune-modulatory compounds would ameliorate disease. GP1681, which suppresses TNF-α, IL-1β, and IL-6, exacerbated CHIK as indicated by increased footpad swelling and viral load. Prophylactic treatment with mDEF201, an adenovirus-vectored interferon, reduced disease, including joint swelling, virus titers at the site of virus challenge and inflammatory cytokines (IL-6, MCP-1, MIP-1α, and RANTES), although efficacy waned as treatment initiation was extended beyond virus challenge. Methotrexate treatment was also effective at ameliorating joint swelling and other disease parameters. Actemra (ACT), an anti-IL-6 antibody, reduced IL-6 levels to baseline, although the resulting improvement in footpad swelling was not significant. Combination therapy with methotrexate and ACT resulted in reduced footpad swelling. Based on our results, immune modulators have potential for the treatment of CHIKV and some of the compounds tested might have potential for clinical developmental.
| Identifer | oai:union.ndltd.org:UTAHS/oai:digitalcommons.usu.edu:etd-6034 |
| Date | 01 May 2016 |
| Creators | Dagley, Ashley L. |
| Publisher | DigitalCommons@USU |
| Source Sets | Utah State University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | All Graduate Theses and Dissertations |
| Rights | Copyright for this work is held by the author. Transmission or reproduction of materials protected by copyright beyond that allowed by fair use requires the written permission of the copyright owners. Works not in the public domain cannot be commercially exploited without permission of the copyright owner. Responsibility for any use rests exclusively with the user. For more information contact Andrew Wesolek (andrew.wesolek@usu.edu). |
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