A Mouse Model of Chikungunya Virus–Induced Musculoskeletal Inflammatory Disease

Abstract

Chikungunya virus (CHIKV), an emerging mosquitoborne Alphavirus, causes debilitating rheumatic disease in humans that can last for weeks to months. Starting in 2004, a CHIKV outbreak in the Indian Ocean region affected millions of people, and infected travelers introduced CHIKV to new regions. The pathogenesis of CHIKV is poorly understood, and no approved vaccines or specific therapies exist. A major challenge to the study of CHIKV disease is the lack of a small animal model that recapitulates the major outcomes of human infection. In this study, the pathogenesis of CHIKV in C57BL/6J mice was investigated using biological and molecular clones of CHIKV isolated from human serum (CHIKV SL15649). After 14-day-old mice were inoculated with CHIKV SL15649 in the footpad, they displayed reduced weight gain and swelling of the inoculated limb. Histologic analysis of hind limb sections revealed severe necrotizing myositis, mixed inflammatory cell arthritis, chronic active tenosynovitis, and multifocal vasculitis. Interestingly, these disease signs and viral RNA persisted in musculoskeletal tissues for at least 3 weeks after inoculation. This work demonstrates the development of a mouse model of CHIKV infection with clinical manifestations and histopathologic findings that are consistent with the disease signs of CHIKV-infected humans, providing a useful tool for studying viral and host factors that drive CHIKV pathogenesis and for evaluating potential therapeutics against this emerging viral disease.

A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection

“…In our study, we analyzed foot swelling and not cell infiltration or tissue damage postchallenge. However, it has been described that, in our infection model, the level of foot swelling postinfection correlates to the level of mononuclear infiltrates and proinflammatory mediators, as well as tissue damage (93,98), supporting the notion that CHIKV arthritis is an inflammatory disease; we therefore assume that the lack of foot swelling observed in mice immunized with MVA-CHIKV reflects a negligible level of local inflammatory cell infiltration and tissue damage. We cannot exclude the possibility that viral replication occurs in the feet, as we have analyzed only CHIKV viremia.…”

“…We cannot exclude the possibility that viral replication occurs in the feet, as we have analyzed only CHIKV viremia. However, it would be difficult to differentiate between the 10 6 PFU CHIKV injected at challenge and the possi-bly newly produced CHIKV, since high levels of viremia are present in feet as long as 9 days after infection (93,98).…”

“…However, adult C57BL/6 mice can be used as a model of CHIKV disease when CHIKV challenge is administered to the footpad (93,98). Thus, to avoid the possibility that normal humoral and cellular immune responses against CHIKV are affected by the lack of a functional IFN-␣/␤ response, we have defined the immunogenicity and efficacy of MVA-CHIKV in C57BL/6 wild-type mice as for other CHIKV vaccine candidates (33,41).…”

γδ T Cells Play a Protective Role in Chikungunya Virus-Induced Disease

“…Detailed sequences and cloning details are available from the authors upon request. The clinical isolate SL15649 has been previously described (68). All studies were performed in certified biological safety level 3 facilities in biological safety cabinets with protocols approved by the University of North Carolina at Chapel Hill Department of Environment, Health and Safety and the Institutional Biosafety Committee.…”

“…Both CD4 ϩ and CD8 ϩ T cells have been shown to infiltrate CHIKV-infected tissues in mouse models of infection (66,68). CD4 ϩ T cells were recently shown to contribute to pathogenesis during CHIKV infection in mice independent of changes in viral titer and IFN-␥ production (69).…”