Alphavirus Pathogenesis and Vaccines
Program Leader: Mark Heise
SE-RP-003: Pathogenesis of Chikungunya virus
University of North Carolina
Chikungunya virus (CHIK) is a mosquito-borne virus capable of causing massive outbreaks of severe arthritis/myositis in infected humans. Though this virus represents a significant emerging disease threat, there are currently no available vaccines or therapeutics and relatively little is known about the pathogenesis of CHIK-induced disease. Progress in this field has been hampered by the lack of suitable small animal models for studying CHIK-induced disease. Therefore, the goal of our research program is to utilize our expertise in the pathogenesis of arthritic alphaviruses to develop an improved model of CHIK-induced arthritis/myositis. We have made significant progress toward this goal by demonstrating that a natural isolate of CHIK induces severe inflammatory arthritis and swelling in the ankle joints of 14 day old C57Bl/6 mice. The model is characterized by inflammatory destruction of the tendons, as well as inflammatory cell infiltration and edema within the synovium. However, the model does have limitations, in that the natural CHIK isolate does not spread very efficiently within the mouse, suggesting that adaptation of the virus to the mouse is required to generate a more robust model of CHIK dissemination and disease. In order to further optimize this model, we are in the process of generating a full length infectious clone based on the sequence of the natural CHIK isolate used in these studies and adapting the virus through repeated passage through the foot and ankle tissue of 24 day old mice to develop a virus that spreads more effectively in the infected mouse and causes disease in older animals. With these tools in hand, we plan to complete the objectives outlined in Aim 1, including 1) determine the sites of viral replication, 2) determine the role of key innate and adaptive immune components in exacerbating or protecting from virus-induced disease. This information will then allow us to determine whether mosquito-derived CHIK exhibits altered replication/disease in the mouse model in Aim 2 and whether mosquito-derived CHIK differs from mammalian cell derived CHIK in its ability initiate host antiviral and inflammatory gene expression in Aim 3. Ultimately, these studies should increase our overall understanding of the relative contribution of viral and host factors in driving CHIK-induced disease and may ultimately lead to the development of new therapies or safer and more effective CHIK vaccines.
