The goal of the proposed research is to reveal structural and mechanistic details of how viral decoy receptors function to enable immune evasion. The focus will be on two gammaherpesvirus proteins, M3 from murine gammaherpesvirus 68 (MHV68) and BARF1 from Epstein-Barr virus (EBV). Both of these secreted proteins are thought to block host immune surveillance mechanisms by sequestering key extracellular mediators of inflammatory response pathways. They are also encoded by novel sequences unrelated to any known host proteins with similar functions. While M3 is a broad-spectrum chemokine binding protein, able to sequester members of all four chemoattractant cytokine families (CC, CXC, CX3C, and C), BARF1 appears to be highly specific for the short-chain helical-bundle cytokine macrophage colony-stimulating factor (CSF-1). Thus, the unmasking of their subterfuge mechanisms will allow for the comparison of promiscuous molecular recognition on the one hand, and highly selective engagement on the other.
These aims will be addressed experimentally through the use of bacterial and baculovirus mediated protein expression, x-ray crystallography, biophysical interaction analysis, and structure-based molecular design. Novel decoy receptor variants will be developed and investigated within a functional context. A detailed mechanistic understanding of the distinct decoy strategies employed by M3 and BARF1 should provide insights into chemokine and cytokine molecular recognition events generally. Further, our experimental results may find application in the control of gammaherpesvirus pathogenesis and, by exploiting similar strategies as these decoy receptors, the development of new agents for the control of inflammatory disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI051426-01A1
Application #
6581065
Study Section
Virology Study Section (VR)
Program Officer
Greenfield, Teri L
Project Start
2002-12-01
Project End
2007-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
1
Fiscal Year
2003
Total Cost
$306,000
Indirect Cost
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Huang, Ren-Huai; Fremont, Daved H; Diener, John L et al. (2009) A structural explanation for the antithrombotic activity of ARC1172, a DNA aptamer that binds von Willebrand factor domain A1. Structure 17:1476-84
Arnold, Phoebe L; Fremont, Daved H (2006) Structural determinants of chemokine binding by an Ectromelia virus-encoded decoy receptor. J Virol 80:7439-49