Alphavirus Pathogenesis and Vaccines
Program Leader: Mark Heise
SE-RP-003: Pathogenesis of Chikungunya virus
University of North Carolina
Chikungunya virus (CHIKV) is a significant emerging pathogen capable of causing massive outbreaks of severe arthritis/myositis in humans The goal of our research project is to develop improved mouse models of CHIKV-induced disease, which will allow us to i) study the pathogenesis of CHIKV-induced disease, ii) determine whether mosquito-derived CHIKV has an advantage over mammalian cell derived virus in establishing infection and causing disease in the mouse, and iii) assess whether mosquito-derived virus differs from mammalian cell derived CHIKV in its ability to induce an antiviral or inflammatory response in vivo and in vitro. We have made significant progress toward the first of these goals, in that we have developed a mouse model where CHIKV infection of adult mice leads to severe arthritis, tenosynovitis, and fasciitis in the feet. We have also found evidence for robust CHIKV replication within the joints of infected mice. This infection elicits an inflammatory response comprised of neutrophils, monocytes, NK cells, and T cells, and CHIKV-induced inflammatory pathology and viral replication persist within infected animals for at least three weeks post infection. Further characterization of which host pathways regulate CHIKV-induced arthritis found that both IL6 and DCIR, an inhibitory C-type lectin receptor, act to limit CHIKV-induced inflammation and damage within infected animals. In addition to characterizing CHIKV-induced disease, we have optimized conditions for producing molecularly cloned alphaviruses from mosquito cells and have generated and characterized a full length infectious clone of a clinical CHIKV isolate. Importantly, this clone-derived virus was able to elicit severe inflammatory disease in infected young and adult mice (greater the six weeks of age). Therefore we have the tools in place to characterize what impact mosquito-derived CHIKV has on disease pathogenesis in adult mice as compared to the mammalian cell derived viruses currently in use. We will also be able to test whether the mammalian or mosquito-derived CHIKV differentially affect the host antiviral and inflammatory responses in infected animals.
