| Abstract: | Chikungunya virus is a mosquito-borne arthrogenic alphavirus that has recently reemerged to produce the largest epidemic ever documented for this virus. Here we describe a new adult wild-type mouse model of chikungunya virus arthritis, which recapitulates the self-limiting arthritis, tenosynovitis, and myositis seen in humans. Rheumatic disease was associated with a prolific infiltrate of monocytes, macrophages, and NK cells and the production of monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ). Infection with a virus isolate from the recent Reunion Island epidemic induced significantly more mononuclear infiltrates, proinflammatory mediators, and foot swelling than did an Asian isolate from the 1960s. Primary mouse macrophages were shown to be productively infected with chikungunya virus; however, the depletion of macrophages ameliorated rheumatic disease and prolonged the viremia. Only 1 μg of an unadjuvanted, inactivated, whole-virus vaccine derived from the Asian isolate completely protected against viremia and arthritis induced by the Reunion Island isolate, illustrating that protection is not strain specific and that low levels of immunity are sufficient to mediate protection. IFN-α treatment was able to prevent arthritis only if given before infection, suggesting that IFN-α is not a viable therapy. Prior infection with Ross River virus, a related arthrogenic alphavirus, and anti-Ross River virus antibodies protected mice against chikungunya virus disease, suggesting that individuals previously exposed to Ross River virus should be protected from chikungunya virus disease. This new mouse model of chikungunya virus disease thus provides insights into pathogenesis and a simple and convenient system to test potential new interventions.Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has caused periodic outbreaks of predominantly rheumatic disease in Africa and Asia (69). The disease usually involves weeks to months of arthralgia/arthritis and can involve myalgia, fever, and/or a rash (6). During 2004 to 2007 the largest documented outbreak of CHIKV disease occurred in Indian Ocean islands and India. Over 260,000 cases (about one-third of the population) were reported in Reunion Island (France) (56), with 1.39 million cases in India (42) and a small outbreak of ∼200 cases also occurring in Italy (56, 74). The recent outbreak was associated with the emergence of a new clade of CHIKV viruses within the large East, Central, and South African phylogroup, which is distinct from the more distantly related Asian phylogroup (52, 55, 62). A key mutation in the E1 gene (A226V) is believed to have allowed efficient CHIKV transmission by Aedes albopictus mosquitoes (13, 76, 80), which were the main vector in the outbreak in Reunion Island and in some parts of India (31). The recent epidemic was associated with a low level of asymptomatic infections and appeared to result in an increase in disease severity compared with that of previous epidemics (8, 51). A small percentage of cases resulted in death (42, 72), although in such cases other underlying medical conditions may have contributed to mortality (14). CHIKV has been declared a high-priority pathogen by the U.S. NIH (60). No licensed vaccine or particularly effective drug is available for human use for any alphavirus (60), although analgesics and nonsteroidal anti-inflammatory drug treatment can provide relief from rheumatic symptoms (48, 68).The development and testing of new interventions are greatly facilitated by the use of mouse models, which can also provide insights into disease pathogenesis (59). Mouse models of CHIKV disease have recently been developed and involve lethal infections of neonatal mice (89) or adult mice defective in the alpha/beta interferon (IFN-α/β) receptor (9). Such models have been used to illustrate the potential utility of treatment with adoptively transferred anti-CHIKV antibodies (10). A third model used intranasal inoculation of CHIKV but showed no rheumatic signs or symptoms (82). All these models used lethality rather than rheumatic manifestations as disease measures. In humans, arthritis/arthralgia is the main manifestation of CHIKV disease, and disease is only rarely fatal (14). The requirement for young mice makes the testing of prophylactic vaccines difficult, as there is insufficient time for vaccination. Human infants also tend not to develop arthritic symptoms following CHIKV infection (78). The use of mice lacking IFN-α/β responses complicates the testing of vaccines and other immunological interventions, as the absence of IFN-α/β signaling can affect both vaccine (26, 77) and virus (60) behaviors.Here we describe the behaviors of two virus isolates of CHIKV, an Asian isolate and a Reunion Island isolate, in a new adult wild-type mouse model of CHIKV arthritis. The Asian isolate was collected in the 1960s in Thailand, and the Reunion Island isolate was collected during the recent outbreak (55). The model produced a measurable self-limiting perimetatarsal foot swelling with clear histological signs of acute and persistent inflammatory disease. We also characterize the cells and inflammatory mediators associated with infection and disease and illustrate the use of the model for studying vaccines, IFN-α therapy, and cross-protection with Ross River virus (RRV), an Australiasian arthrogenic alphavirus related to CHIKV (16, 69). |
