Protection against Chikungunya virus induced arthralgia following prophylactic treatment with adenovirus vectored interferon (mDEF201).
Recent outbreaks of Chikungunya virus (CHIKV) infection have resulted in millions of cases of disease with significant morbidity. No approved antiviral treatments exist for the prevention or treatment of this viral disease. Infection with CHIKV results in a high rate of symptomatic disease that primarily includes a debilitating arthralgia. To model this cardinal disease manifestation, adult DBA/1J mice were challenged with CHIKV by footpad injection. Viremia and hind limb virus titers increased ∼100-fold while spleen virus increased >1000-fold within 1day post-virus infection (dpi). Footpad swelling was measured over a 10-day period, with peak swelling observed between 6 and 7dpi. Histology of the hind leg at the site of virus challenge showed evidence of myositis and synovitis starting on 5dpi. Cytokine profiling of the hind limb at the site of inoculation revealed a biphasic inflammatory response represented by an increase in IL-6, MCP-1, IFN-γ, MIP-1α, RANTES, and IL-17. To investigate the prophylactic capacity of IFN, mice were treated with mDEF201, an adenovirus-vectored IFN-α. Intranasal administration of a single 10(7)pfu/ml dose of mDEF201 administered 21days to 24h prior to infection, significantly reduced footpad swelling, virus titers in the hind leg and spleen, and several inflammatory cytokines. Efficacy was not observed when treatment was initiated 24h after virus challenge. This arthralgia model of CHIKV recapitulates relevant disease features commonly observed in human disease making it applicable to preclinical testing of therapies that target both viral replication and the associated joint disease.
Institute for Antiviral Research, Utah State University, Logan, UT 84335, United States.
Ashley
A
Dagley
Defyrus, Inc., 2 Bloor Street W, Suite 2602, Toronto, ON M4W 3E2, Canada.
Jane
J
Ennis
Defyrus, Inc., 2 Bloor Street W, Suite 2602, Toronto, ON M4W 3E2, Canada.
Jeffrey D
JD
Turner
Animal, Dairy and Veterinary Sciences Department, Utah State University, Logan, UT 84335, United States.
Kerry A
KA
Rood
Animal, Dairy and Veterinary Sciences Department, Utah State University, Logan, UT 84335, United States; Utah Veterinary Diagnostic Laboratory, Utah State University, Logan, UT 84335, United States.
Arnaud J
AJ
Van Wettere
Institute for Antiviral Research, Utah State University, Logan, UT 84335, United States.
Brian B
BB
Gowen
Institute for Antiviral Research, Utah State University, Logan, UT 84335, United States. Electronic address: justin.julander@usu.edu.
Justin G
JG
Julander
D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D018771:Arthralgia / Q000473:pathology / Q000517:prevention & control*; D001691:Biological Therapy / Q000379:methods*; D065632:Chikungunya Fever / Q000150:complications* / Q000473:pathology / Q000628:therapy*; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage*; D006651:Histocytochemistry; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000235:genetics; D008811:Mice, Inbred DBA; D009220:Myositis / Q000473:pathology; D013154:Spleen / Q000821:virology; D013585:Synovitis / Q000473:pathology; D019562:Viral Load
D016207:Cytokines; D004337:Drug Carriers; D016898:Interferon-alpha
Antiviral; Arthritis; Chikungunya; Interferon; Mouse model; mDEF201