This proposal will use the interferon-? binding protein from ectromelia virus (IFN-?BPECTV) to design new cytokine antagonists and improved research reagents with broad applications to many disciplines. Preliminary structural studies on IFN-?BPECTV have revealed a novel tetrameric structure. The structure will be used to engineer IFN-?BPECTV-based reagents that block signaling by the immunosuppressive cytokine, IL-10. These poxvirus-based IL-10 blocking proteins will be tested for their ability to resolve chronic LCMV infections in mice. Using computational and library screening methodology, hetero-tetrameric D3 assembly reagents will also be developed and tested in the LCMV infection model. These studies will validate the importance of D3-based reagents and provide new insights into LCMV induced T-cell exhaustion. This is important as T-cell exhaustion also occurs during hepatitis C and HIV infections in humans.
This proposal will design and test cytokine blocking reagents that are based on proteins in poxviruses that efficiently antagonize cytokines. This work will provide new research reagents to better study T-cell exhaustion and a broad number of other problems in human health. In particular, these studies could help us understand how to harness the immune system to eliminate hepatitis C and/or HIV infections.
| Deshpande, Ashlesha; Putcha, Balananda-Dhurjati Kumar; Kuruganti, Srilalitha et al. (2013) Kinetic analysis of cytokine-mediated receptor assembly using engineered FC heterodimers. Protein Sci 22:1100-8 |
| Donnelly, Raymond P; Sheikh, Faruk; Dickensheets, Harold et al. (2010) Interleukin-26: an IL-10-related cytokine produced by Th17 cells. Cytokine Growth Factor Rev 21:393-401 |
