Research Programs














Alphavirus Pathogenesis and Vaccines

Program Leader: Mark Heise


SE-RP-003: Pathogenesis of Chikungunya virus

Mark Heise

University of North Carolina

Chikungunya virus (CHIKV) is mosquito-borne virus associated with large outbreaks of severe acute and persistent arthritis.  Though CHIKV causes severe human disease, there are currently no vaccines or therapies for the treatment of CHIKV-induced arthritis, and the development of these therapies/vaccines requires an improved understanding of CHIKV pathogenesis.  Therefore, we have developed a mouse model of CHIKV-induced disease with the goal of using this system to improve our understanding of the pathogenesis of CHIKV-induced arthritis.  Specifically, we have been using these models to investigate which host pathways play a role in either protecting from or exacerbating CHIKV-induced disease, while probing the impact of viral glycosylation on CHIKV cell tropism and the host antiviral/pro-inflammatory response.  In the past year, we have further improved our mouse models by selecting for a mouse adapted CHIKV that exhibited an enhanced ability to spread and replicate in joint tissues within the mouse.  We have also found that CHIKV-infection leads to the recruitment of CD11c positive dendritic cells into early sites of CHIKV infection and that these cells are a site of CHIKV replication.  Ongoing studies are evaluating what role these CHIKV/dendritic cell interactions play in the early stages of CHIKV infection and subsequent development of the virus-induced inflammatory response.  As part of this study, we have begun to evaluate whether the N-linked glycans on the viral E2 glycoprotein, which are required for the development of CHIKV-induced arthritis, are affecting the tropism of CHIKV for these dendritic cells or the functional activity of these cells after CHIKV infection.  Importantly, we found that CHIKV lacking both N-linked glycans on the E2 glycoprotein still replicated to wild type levels within stromal cells within the feet of infected mice, but showed a deficit in its ability to replicate within the infiltrating dendritic cells.  Since this virus is defective in its ability to cause disease, this suggests that CHIKV replication within DCs may play a major role in driving virus induced disease.  Studies are currently underway to directly test this possibility.  Lastly, we have been evaluating the role of specific host innate and adaptive immune components in either limiting or exacerbating CHIKV-induced disease.  These studies have found that DCIR, an inhibitor C-type lectin receptor found on dendritic cells and other immune cell types, limits the severity of CHIKV-induced swelling and inflammatory damage.  Likewise, gamma/delta T cells play a protective role during CHIKV infection, since mice lacking gamma/delta T cells or animals treated with an anti-gamma/delta T cell antibody develop enhanced swelling following CHIKV infection.  Ongoing studies are evaluating whether other C-type lectin receptors also regulate CHIKV-induced disease severity and whether DCIR or other molecules are directly affecting gamma/delta T cell function in CHIKV infected animals.