The Skaggs Institute for Chemical Biology
Faculty, Graduate Program
Structural Studies of the Immune System, Viral Pathogens, and Vaccine Design
Immunologic recognition of microbial pathogens is fundamental for fighting infectious disease. Our major goal is to understand the interaction and neutralization of foreign antigens by the immune system through high-resolution x-ray structural studies of antibodies, Variable Lymphocyte Rectors (VLRs) and antigens in the humoral system, T-cell receptor complexes with MHC class I and class II in the cellular system, and through pattern recognition receptors, such as TLRs, in the innate immune system.
Over112 crystal structures of monoclonal Fab fragments and complexes with a variety of antigens, such as peptides, steroids, cocaine, and proteins, including HIV-1, gp120 and gp41, have led to significant insights into antibody-antigen recognition, virus neutralization, and vaccine design for HIV-1. In addition, catalytic or fluorescent antibodies, many of which carry out disfavored reactions or for which no natural enzymes exist, or have interesting physico-chemical properties have given us insight into a myriad of uses as artificial catalysts or as biosensors. The T-cell receptor in complex with pMHC has revealed how peptide antigens can be recognized in the context of the MHC molecule. Many other key molecules in cellular immunology are being studied, such as non-classical or MHC homologues: for example, CD1 binds lipid, glycolipid, and lipopeptide antigens from the cell walls of microbial pathogens and the NK family of receptors recognizes classical as well as distant MHC homologues. Studies on other pattern recognition receptors, include peptidoglycan recognition protein (PGRP), TREM-1, Toll-like receptors (TLR) have revealed how unique pathogen-associated molecules are recognized by the immune system.
Much of our recent work is focused on HIV-1 and influenza viruses. The 1918 flu, which killed 20-40 million people worldwide, is being investigated through structural and binding studies of the 1918 viral proteins, such as the hemagglutinin (HA) and neuraminidase, as well as other the viral proteins. The avian H5N1 and swine H1N1 influenza virus HA structures have been determined as well as mutations that enhance binding to human receptors that may allow the virus to cross the species barrier into humans and be transmissible. We have also determined structures of almost all of the rare, broadly neutralizing antibodies against the HIV-1 envelope proteins, gp120 and gp41, in order to elucidate the sites of vulnerability that can be used for HIV-1 vaccine design. A very exciting project on broadly neutralizing antibodies with influenza virus has revealed novel epitopes that are of great value for structure-assisted vaccine development. We have defined a broadly neutralizing epitope in all group 1 influenza subtypes and are working on other antibodies that recognize group 2 as well as those that cross all subtypes. Other flu projects are associated with the nucleoproteins, polymerases and neuraminidases in order to understand how influenza replicates.
Finally, I direct the Joint Center for Structural Genomics that pioneers new high throughput methodologies and technologies for protein production, structure determination and functional analysis in order to investigate the Expanding Protein Universe and the human gut microbiome and other high-value targets in the regulation of stem cells and T cells.
D.Sc., Biology, University of Oxford, 2000
Fellow, Royal Society of London Fellow, Royal Society of Edinburgh Board of Directors and Scientific Advisory Board, Keystone Symposia Associate Editor, Journal of Molecular Biology, Immunity Editorial Boards, Science , Journal of Experimental Medicine Director of the NIGMS Joint Center for Structural Genomics
Xu, R., Ekiert, D. C., Krause, J. C., Hai, R., Crowe, J. E., Jr., and Wilson, I. A. (2010) Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus. Science 328:357-360.
Verdino, P., Witherden, D. A., Havran, W. L., and Wilson, I. A. (2010) The molecular interaction of CAR and JAML recruits the central cell signal transducer PI3K. Science 329:1210-1214. PMC ID: 2951132
Ekiert, D. C., Bhabha, G., Elsliger, M. A., Friesen, R. H., Jongeneelen, M., Throsby, M., Goudsmit, J., and Wilson, I. A. (2009) Antibody recognition of a highly conserved influenza virus epitope. Science 324:246-251.
Han, B.W., Herrin, B.R., Cooper, M.D., Wilson, I.A. (2008) Antigen recognition by variable lymphocyte receptors. Science 321:1834-1837.
Stevens J., Blixt O., Tumpey T.M., Taubenberger J.K., Paulson J.C., Wilson I.A. (2006) Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 312:404-410.
Choe J., Kelker M.S., Wilson I.A. (2005) Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309:581-585.