15. InnateDB  Developed  to  Aid  Two  Large  Interna4onal     Systems  Biology  Projects   Mouse Model Datasets: Cerebral Malaria mouse model (IMR, Australia) Tuberculosis mouse model (AECM) Shigella xenograft model (Pasteur) Human Clinical Datasets: Typhoid & Malaria Vietnam (OUCRU/Stanford/ Sanger) Non Typhoidal Salmonella Malawi (Sanger)+ Chronic/Acute Helminth Ecuador (USF de Quito/ Sanger) Dengue (OUCRU) Modulating innate immune response via Host Defense peptides (Hancock lab, UBC) Mouse KOs (Sanger) Novel insight into host response and mechanism of peptides. Common Pathways, networks and transcriptional regulation. Thompson et al PNAS December 2009
16. Systems Biology & The Innate Immune Response:  Many layers of complexity.  Layers of regulation: transcriptional; post-transcriptional (miRNAs); post-translational (ubiquitination, phosphorylation)  Host-pathogen interactions  100s – 1000s DE genes  Not simple pathways - networks of molecular interactions Gardy*, Lynn*, Brinkman, Hancock (2009). Enabling a systems biology approach to immunology: focus on innate immunity. Trends in Immunology PMID: 19428301
17. Breuer et al., 2013 InnateDB: systems biology of innate immunity and beyond… NAR (DB issue) PMID: 23180781
18. Manual Curation of Interaction Data From Literature to Database Greatly Enhances Coverage of Innate Immunity Interactome INNATEDB CURATED INTERACTOME INTERACTIONS INTERACTIONS ONLY CURATED ALSO CURATED BY INNATEDB BY TOP 5 OTHER INTERACTION DATABASES: BIND, INTACT, DIP, BIOGRID & MINT Lynn et al., Curating the Innate Immunity Interactome. BMC Systems Biology 2010 PMID: 20727158
19. Manual  Cura4on  of  Interac4on  Data  From  Literature  to  Database  –  Enhancing  coverage  of  Innate  Immunity  Interactome   The  InnateDB  curated   interactome  in  July  2012.   Red  edges  represent   interac4ons  that  have  been   added  in  2011  and  2012.   Breuer et al., 2013 InnateDB: systems biology of innate immunity and beyond… Nucleic Acids Research (Database issue)
20. Contextually Curating Innate Immunity-Relevant InteractionsAnnotated fields include:Molecule type; organism;biological role; interactiondetection method; thehost system (in vitro, invivo, ex vivo); hostorganism; interactiontype; cell, cell-line andtissue types; cell status(primary/cell line);experimental role;participant identificationmethod and sub-cellularlocalization, plus varietyof additional curatorcomments.
21. Curating Innate Immunity-Relevant Interactions  71% human, 22% mouse, 7% human- mouse  ~80% interactions in innate immunity interactome not annotated by other major databases  Protein (69%), DNA and RNA interactions  Developed InnateDB submission system software to allow submission of interaction annotation in an OBO ontology-controlled and MIMIx & PSI-MI 2.5 compliant manner. Lynn et al., Curating the Innate Immunity Interactome. BMC Systems Biology 2010 PMID: 20727158
22. Which journals are curated?  >4,400 journal articles curated to date  Don’t focus on specific journals - relevant articles curated if meet appropriate quality standards for the interaction evidence.  Indeed, at least one protein has been curated from >200 different journals.  More than 70% of curated articles have come from 20 journals.  Note many journals in top 20 are not “immunology journals”, underscoring importance of not limiting curation efforts to journals perceived as “relevant”.
23. Curating Innate Immunity-Relevant Interactions – 4-pronged approach  Curation  primarily pathway-centric   systematically review all literature describing interactions for a particular innate immunity pathway.   Curate all other interactors regardless of whether the interacting molecule is a member of the pathway or has any known role in innate immunity  expands network outside of known innate immunity players.   Systematically curated pathways are scheduled for frequent re-curation as the field is moving quickly.  Also, new publications on innate immunity assessed on a daily basis to identify novel interactions of interest.   Priority given to the most recent publications  incorporates new information on the most current research  Immunology Community-aided:   Curators consult with researchers to confirm unclear literature data   Most common issue: Unclear what species the protein/DNA/RNA interactors come from  Curation Community-aided:   InnateDB curators review each others curations as an error check   IMEx consortium! http://www.innatedb.com/doc/InnateDB_2010_curation_guide.pdf
25. Going Beyond Innate Immunity – An Integrative Biology Resource  >196,000 human and mouse interactions extracted & loaded from BIND, INTACT, DIP, BIOGRID & MINT DBs  Cross-referenced genes to >3,000 pathways from KEGG, PID, BIOCARTA, INOH, NetPath & Reactome DBs   Visualize/analyze interactions associated with specific pathway   Pathway over-representation analysis  Ensembl annotation provides details of all human & mouse genes/transcripts/ proteins. UniProt, Entrez, Gene Ontology, etc  rich protein & gene annotation  Transcript. factor–DNA interactions experimentally confirmed from Transfac, TransCompel  Robust orthology & gene synteny analysis facilitate human-mouse comparisons
27. InnateDB  –  Facilita4ng  Systems-­‐Level  Analyses  of  Gene  Expression  Data   Upload Your Own Gene Expression Data - Up to 10 conditions/timepoints at 1 time.Overlay Gene Expression Data Pathway, Gene Ontology & TF ORA tools from Multiple Conditions on Find – DE Pathways/Functionally Related Networks/Pathways Genes/TFs Go Beyond Pathway Analysis – Differentially Expressed Sub-networks – New Pathways? How Are DE Genes Actually Inter-connected? Central Regulators (Network Hubs)
28. InnateDB and curated data aided study of an immune modulator – host-directed adjunctive therapy coupled with anti-malarial