Pathogens use structural mimicry of native host ligands as a mechanism for host receptor engagement.

A pathogen's ability to engage host receptors is a critical determinant of its host range and interspecies transmissibility, key issues for understanding emerging diseases. However, the identification of host receptors, which are also attractive drug targets, remains a major challenge. Our structural bioinformatics studies reveal that both bacterial and viral pathogens have evolved to structurally mimic native host ligands (ligand mimicry), thus enabling engagement of their cognate host receptors. In contrast to the structural homology, amino acid sequence similarity between pathogen molecules and the mimicked host ligands was low. We illustrate the utility of this concept to identify pathogen receptors by delineating receptor tyrosine kinase Axl as a candidate receptor for the polyomavirus SV40. The SV40-Axl interaction was validated, and its participation in the infection process was verified. Our results suggest that ligand mimicry is widespread, and we present a quick tool to screen for pathogen-host receptor interactions.

[1]  Thilo Stehle,et al.  Structural basis of GM1 ganglioside recognition by simian virus 40 , 2008, Proceedings of the National Academy of Sciences.

[2]  V. Butin‐Israeli,et al.  Simian Virus 40 Infection Triggers a Balanced Network That Includes Apoptotic, Survival, and Stress Pathways , 2010, Journal of Virology.

[3]  B. Honig,et al.  Structure-based prediction of protein-protein interactions on a genome-wide scale , 2012, Nature.

[4]  Anne Imberty,et al.  N-Glycolyl GM1 Ganglioside as a Receptor for Simian Virus 40 , 2007, Journal of Virology.

[5]  Ruth Nussinov,et al.  PatchDock and SymmDock: servers for rigid and symmetric docking , 2005, Nucleic Acids Res..

[6]  Petra Schwille,et al.  GM1 structure determines SV40-induced membrane invagination and infection , 2010, Nature Cell Biology.

[7]  Bianca Habermann,et al.  Genome-wide analysis of human kinases in clathrin- and caveolae/raft-mediated endocytosis , 2005, Nature.

[8]  G. Lemke,et al.  TAM Receptors Are Pleiotropic Inhibitors of the Innate Immune Response , 2007, Cell.

[9]  G. Gao,et al.  Binding of herpes simplex virus glycoprotein D to nectin-1 exploits host cell adhesion. , 2011, Nature communications.

[10]  W. Atwood,et al.  Class I major histocompatibility proteins are an essential component of the simian virus 40 receptor , 1992, Journal of virology.

[11]  D. Lublin,et al.  Characterization of the echovirus 7 receptor: domains of CD55 critical for virus binding , 1995, Journal of virology.

[12]  W. Atwood,et al.  Class I major histocompatibility proteins as cell surface receptors for simian virus 40 , 1989, Journal of virology.

[13]  J. Galán,et al.  Common themes in the design and function of bacterial effectors. , 2009, Cell host & microbe.

[14]  J. Mercer.  Viral apoptotic mimicry party: P.S. Bring your own Gas6. , 2011, Cell host & microbe.

[15]  C. Sander,et al.  Dali: a network tool for protein structure comparison. , 1995, Trends in biochemical sciences.

[16]  P. Spear,et al.  Herpes simplex virus: receptors and ligands for cell entry , 2004, Cellular microbiology.

[17]  Jorge E. Galán,et al.  Structural mimicry in bacterial virulence , 2001, Nature.

[18]  A. Siitonen,et al.  A widespread outbreak of Yersinia pseudotuberculosis O:3 infection from iceberg lettuce. , 2004, The Journal of infectious diseases.

[19]  H. Earp,et al.  TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. , 2008, Advances in cancer research.

[20]  Liisa Holm,et al.  Dali server: conservation mapping in 3D , 2010, Nucleic Acids Res..

[21]  G. Lemke,et al.  TAM receptors and the clearance of apoptotic cells , 2010, Annals of the New York Academy of Sciences.

[22]  Uri Raviv,et al.  RNA encapsidation by SV40-derived nanoparticles follows a rapid two-state mechanism. , 2012, Journal of the American Chemical Society.

[23]  Ilya A Vakser,et al.  Low-resolution structural modeling of protein interactome. , 2013, Current opinion in structural biology.

[24]  U. Landegren,et al.  Direct observation of individual endogenous protein complexes in situ by proximity ligation , 2006, Nature Methods.

[25]  J. Chu,et al.  Interaction of West Nile Virus with αvβ3 Integrin Mediates Virus Entry into Cells* , 2004, Journal of Biological Chemistry.

[26]  Thilo Stehle,et al.  Crystal Structure of the Extracellular Segment of Integrin αVβ3 in Complex with an Arg-Gly-Asp Ligand , 2002, Science.

[27]  A. Oppenheim,et al.  Self-assembly and protein-protein interactions between the SV40 capsid proteins produced in insect cells. , 1997, Virology.

[28]  Thilo Stehle,et al.  Gangliosides are receptors for murine polyoma virus and SV40 , 2003, The EMBO journal.

[29]  A. Sahu,et al.  Viral mimicry of the complement system , 2003, Journal of Biosciences.

[30]  S. Mukherjee,et al.  Reproductive toxicology. Diethylstilbestrol. , 1997, Environmental health perspectives.

[31]  A. Kolokoltsov,et al.  The Tyro3 Receptor Kinase Axl Enhances Macropinocytosis of Zaire Ebolavirus , 2010, Journal of Virology.

[32]  E. Galun,et al.  Liver-targeted gene therapy by SV40-based vectors using the hydrodynamic injection method. , 2005, Human gene therapy.

[33]  A. Ponsonby,et al.  Epstein–Barr virus and multiple sclerosis , 2011, Journal of Neurology, Neurosurgery & Psychiatry.

[34]  R. Eisenberg,et al.  Herpes Simplex Virus Glycoprotein D Interferes with Binding of Herpesvirus Entry Mediator to Its Ligands through Downregulation and Direct Competition , 2010, Journal of Virology.

[35]  S. Moseley,et al.  Escherichia coli DraE Adhesin-Associated Bacterial Internalization by Epithelial Cells Is Promoted Independently by Decay-Accelerating Factor and Carcinoembryonic Antigen-Related Cell Adhesion Molecule Binding and Does Not Require the DraD Invasin , 2008, Infection and Immunity.

[36]  B. H. Rosenberg,et al.  Growth and purification of SV40 virus for biochemical studies. , 1981, Journal of virological methods.

[37]  M. Feitelson,et al.  Use of SV40 to immunize against hepatitis B surface antigen: implications for the use of SV40 for gene transduction and its use as an immunizing agent , 1998, Gene Therapy.

[38]  L. Pelkmans,et al.  Integrin-Mediated Signaling Induced by Simian Virus 40 Leads to Transient Uncoupling of Cortical Actin and the Plasma Membrane , 2013, PloS one.

[39]  T. Shimi,et al.  Simian virus 40 induces lamin A/C fluctuations and nuclear envelope deformation during cell entry , 2011, Nucleus.

[40]  P. Bois,et al.  Shigella applies molecular mimicry to subvert vinculin and invade host cells , 2006, The Journal of cell biology.

[41]  Stephen R Quake,et al.  An in vitro microfluidic approach to generating protein-interaction networks , 2009, Nature Methods.

[42]  Y. Kawaoka,et al.  Identification of Cell Surface Molecules Involved in Dystroglycan-Independent Lassa Virus Cell Entry , 2011, Journal of Virology.

[43]  Yair Glick,et al.  Microfluidic large scale integration of viral-host interaction analysis. , 2013, Lab on a chip.

[44]  C. Ware,et al.  B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator , 2005, Nature Immunology.

[45]  A. Oppenheim,et al.  Rapid method for SV40 titration. , 2010, Journal of virological methods.

[46]  C. Benedict.  Viruses and the TNF-related cytokines, an evolving battle. , 2003, Cytokine & growth factor reviews.

[47]  Dawen Cai,et al.  A Lipid Receptor Sorts Polyomavirus from the Endolysosome to the Endoplasmic Reticulum to Cause Infection , 2009, PLoS pathogens.

[48]  A. Wu,et al.  The soluble serum protein Gas6 bridges virion envelope phosphatidylserine to the TAM receptor tyrosine kinase Axl to mediate viral entry. , 2011, Cell host & microbe.

[49]  N. Stanietsky,et al.  The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity , 2009, Proceedings of the National Academy of Sciences.

[50]  R. Isberg,et al.  Multiple β 1 chain integrins are receptors for invasin, a protein that promotes bacterial penetration into mammalian cells , 1990, Cell.

[51]  Charles L. Brooks,et al.  Viral Capsid Proteins Are Segregated in Structural Fold Space , 2013, PLoS Comput. Biol..

[52]  T. Stehle,et al.  Structure of Adenovirus Type 21 Knob in Complex with CD46 Reveals Key Differences in Receptor Contacts among Species B Adenoviruses , 2010, Journal of Virology.

[53]  Mark Yeager,et al.  Three-dimensional EM structure of the ectodomain of integrin αVβ3 in a complex with fibronectin , 2005, The Journal of cell biology.

[54]  Nels C. Elde,et al.  The evolutionary conundrum of pathogen mimicry , 2009, Nature Reviews Microbiology.

[55]  Liisa Holm,et al.  Advances and pitfalls of protein structural alignment. , 2009, Current opinion in structural biology.

[56]  R. Manetti,et al.  Infectious diseases and autoimmunity. , 2011, Journal of infection in developing countries.

[57]  O. Schueler‐Furman,et al.  The SV40 capsid is stabilized by a conserved pentapeptide hinge of the major capsid protein VP1. , 2009, Journal of molecular biology.

[58]  Antonio Alcami,et al.  Viral mimicry of cytokines, chemokines and their receptors , 2003, Nature Reviews Immunology.

[59]  R. Timpl,et al.  Structural basis for Gas6–Axl signalling , 2006, The EMBO journal.