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© Michel Huerre
Coupe histologique de foie de patient atteint d'une hépatite C chronique active avec infiltrat (opacité) folliculaire (lymphocytes) (Grossissement X 400). L'hépatite C chronique peut être à l'origine de cirrhose et cancer du foie

About

integrative-interactomics“Our goal is to find and understand the links between virus and host genotypes, phenotypes and pathogenic traits using comparative interactomics and bioinformatics”

It is commonly admitted that identifying protein interaction network “interactomes” has shed light on the organizing principles of living cells by providing key insights into understanding how cellular components work together. Interactome mapping thus enables deeper mechanistic understanding of the cell: a major objective of systems biology. Our work falls within the scope of an emerging discipline at the convergence of virology and systems biology. Since the completion of the human genome, steps forward in massively parallel interactome-mapping pipelines using next-generation sequencing have enabled generation of more comprehensive human interactome datasets. Similarly, mapping of intracellular interactions between viral and cellular components is strongly relevant to understanding how viruses hijack cellular functions, control and escape antiviral mechanisms, and ultimately achieve replication and spreading including in new host species. We have developped a new strategy, comparative interactomics, to identify specific signatures, that correlate interaction datasets, protein sequences and structural informations with pathogenic traits,

Our team has  pioneered decipherment of virus-host interactomes “virhostomes” using high-throughput innovative technologies including state-of-the-art yeast two-hybrid and orthogonal protein-protein or protein-nucleic acid interaction assays such as split-luciferase based complementation assays in human cells and other pull-down methods.

Our main project aims to generate exhaustive proteome scale interactomics datasets for major public health concern respiratory viruses, particularly influenza viruses. This effort includes comparative interactomics between viral strains and host species. Given that a major pathway of protein modification in eukaryotic cells, the Ubiquitin Proteasome System “UPS”, is a prime target of most viruses, we are currently implementing a UPS dedicated interactomic study mapping interactions between hundreds of UPS human ORFs and a representative collection of influenza viruses.

For in depth, multi-species mapping of virus-host protein interactions we are developing a next generation massively parallel yeast two-hybrid system. This pioneering methodology will allow us to generate, at a large scale and with statistically reliable sampling, exhaustive interactomics datasets. Comparative studies involving numerous viral strains, variants of a given strain, and various host species, will allow to characterize the viral mutations that modify protein interactomic properties, the so called “edgotypic mutations”.

Differential viral interactomes will be connected into the next prototypical human interactome in order to understand how their mutual interplay leads to emergent system properties that represent specific features of viral pathogenesis.

Keywords : Systems biology, Comparative Interactomics, Virhostome, protein-protein interaction, yeast two-hybrid, High-throughput screening, protein complementation assay

External collaborators

Center for Cancer Systems Biology(CCSB): http://ccsb.dfci.harvard.edu/web/www/ccsb/
ROTH laboratory: http://llama.mshri.on.ca/
LINDQUIST laboratory: http://lindquistlab.wi.mit.edu/
RUAL laboratory: http://www.pathology.med.umich.edu/index.php?t=page&id=721
BAR-ZIV laboratory: http://www.weizmann.ac.il/materials/barziv/
EINAV laboratory: http://med.stanford.edu/profiles/Shirit_Einav/
Oncoproteins laboratory-ESBS: http://irebs.u-strasbg.fr/spip.php?rubrique62
Center of Excellence in Genomic Science (CEGS-CCSB): http://cegs.dfci.harvard.edu/
Center for Complex Network Research( CCNR): http://www.barabasilab.com/
Bioinformatics and Functional Genomics Research Group: http://bioinfow.dep.usal.es/
Seidah Laboratory (IRCM-Montréal): http://www.ircm.qc.ca/LARECHERCHE/AXES/MALADIES/BIONEURO/PAGES/PROJETS.ASPX?PFLG=1033&lan=1033

Links

Bioinformatic and Experimental Research in the field of Network and Systems Biology:
IDEKER laboratory: http://idekerlab.ucsd.edu/Pages/default.aspx
CALIFANO laboratory: http://wiki.c2b2.columbia.edu/califanolab/index.php/Main_Page
REGEV laboratory: http://wiki.c2b2.columbia.edu/califanolab/index.php/Main_Page
MANOLIS laboratory: http://web.mit.edu/manoli/
ALON laboratory: http://www.weizmann.ac.il/mcb/UriAlon/
EISENBERG laboratory: http://www.doe-mbi.ucla.edu/People/Eisenberg/
Center for Systems Biology-MGH: http://www.massgeneral.org/csb/
Institute for Systems Biology: https://www.systemsbiology.org/
Center for Genome Sciences and Systems Biology-Washington University: http://genomesciences.wustl.edu/
Luxembourg Centre for Systems Biomedicine: http://uni.lu/lcsb
The Berlin Institute for Medical Systems Biology: https://www.mdc-berlin.de/13800178/en/bimsb
Institute of Molecular Systems Biology: http://www.imsb.ethz.ch/
European Institute for Systems Biology and Medicine: http://www.eisbm.org/
Interdisciplinary Center for scientific Computing: http://www.iwr.uni-heidelberg.de/

Proteomics:
BLAIS proteomics center: http://blais.dfci.harvard.edu/
Proteomics- Institut Jacques Monod: http://www.ijm.fr/plateformes/spectrometrie-de-masse/
GIBSON laboratory-EMBL: http://www.embl.de/research/units/scb/gibson/
Baker laboratory: http://depts.washington.edu/bakerpg/drupal/

Resources:
Cytoscape: http://www.cytoscape.org/
ViralORFeome : http://pbildb1.univ-lyon1.fr/viralorfeome/index.php
hORFeome: http://horfdb.dfci.harvard.edu/
ConsensusPathDB: http://cpdb.molgen.mpg.de/
Bioinformatics and research computing-Whitehead Institute: http://jura.wi.mit.edu/bio/
Cell circuits: http://www.cellcircuits.org/search/index.html
STRING-Functional Protein Association Networks: http://string-db.org/
DAVID Bioinformatics Resources: http://david.abcc.ncifcrf.gov/
INTACT: http://www.ebi.ac.uk/intact/
Molecular Interaction Database- MINT: http://mint.bio.uniroma2.it/mint/Welcome.do
Clustering-EISEN laboratory: http://www.eisenlab.org/eisen/
Eukaryotic Linear Motif: http://elm.eu.org/
Information Hyperlinked Over Proteins: http://www.ihop-net.org/UniPub/iHOP/
RCSB protein database: http://www.rcsb.org/pdb/home/home.do
ENSEMBL: http://www.ensembl.org/index.html
UNIPROT: http://www.uniprot.org/
Genetic Association Studies-GWAS: https://www.gwascentral.org/
COSMIC-Cancer Gene Census: http://cancer.sanger.ac.uk/cancergenome/projects/census/
Mendelian Inheritance in Man-OMIM: http://www.omim.org
See more at: http://www.pasteur.fr/en/research/virology/units-groups/molecular-genetics-rna-viruses/research/systems-biology-respiratory-viruses-infections#sthash.uHrjgsp6.dpuf

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