The Mycobacterium tuberculosis SysBorg

1. The Mycobacterium tuberculosis SysBorg Joint Indo-Russian Workshop «Systems Biology and Genome Informatics of M. tuberculosis and other infectious diseases» October, 13-14 2008 г. Institute of Cytology and Genetics SB RAS, Novosibirsk

2. Life from the perspective of the pathogen Questions in Tuberculosis Express antivirulence; Hide Latent stage Latency? Battle lost Subvert Host signalling; live within the enemy Pi Immune clearance? N Infection process? M. tuberculosis entering a macrophage Find surface receptors and enter; Friendship

3. Pathogen GENOME FINALIZATION OF ORFs (CONSIDER EXPRESSION ISSUES) PROTEIN PRODUCED ORFs CLONING PROTEINSEQUENCES TARGET VALIDATION SIMILARITY SEARCH ALGORITHMS BLAST, PLHoST, BLASTCLUST,… BIOCHEMICAL ASSAY BIOPHYSICAL ASSAY FUNCTION PREDICTION IN SILICO TARGET ASSESSMENT TARGET SELECTION ALGORITHMS INVARIANT PEPTIDES, HIGH COST, PATHOGEN(+) AND HUMAN(-), PDB, SURFACE PREDICTION STEPS TO DRUG DISCOVERY USING M. tuberculosis SysBorg

4. Pathogen GENOME FINALIZATION OF ORFs (CONSIDER EXPRESSION ISSUES) PROTEIN PRODUCED ORFs CLONING PROTEINSEQUENCES SURFACE LOCALIZATION ALGORITHMS PSORT, SPAAN, MAAP,… IN SILICO CANDIDATE ASSESSMENT USE ANIMAL MODELS SURFACE PREDICTION USING M. tuberculosis SysBorg FILTERING ALGORITHMS EPITOPE PREDICTION, ALLERGENS, ANTIGENIC REGIONS, TRANSMEMBRANE REGIONS PATHOGEN(+) AND HUMAN(-), PDB STEPS TO VACCINE DISCOVERY

5. The Events A first version of structure of SysBorg platform prepared. This had fixed number of Fields Co-ordinator assigned. Partnership with SilicoGene, Industry established Chairman, proposes a networked initiative for tuberculosis A Flexible architecture proposed, where the numbers of Fields, Tables and Units were made flexible Windows version Combination query samples generated applying boolean and arithmetic operators A Brainstorming session was held Scientists & students collect curated data in structured format Data Plugged in to the platform LINUX version also developed

6. Construction of M. tuberculosis SysBorg is a Mega Project

7. Networking of expert scientists at the national level HK RC SKB DD BS BKM CNM BP RR VB M. tuberculosis SysBorg SR MB BKM YS GPSR SG SM SC RS CSIR NETWORKED TEAM EFFORT

8. IMTECH CDRI RRLJ IICB Other partners ACBR VPCI NII M. tuberculosis SysBorg : A systems Biology platform for infectious diseases using Systems Biology of whole organism How does Latency arise Fumarate FAD What does M.tb do during infection ATP NADH Coenzyme A How does M.tb infect Y Y How is the pathogen cleared Metabolic and Signalling Network ( CSIR Task force Network for in silico drug target discovery )

9. Activity structuring Blocks strainpoly annotation drugs geneexpress hostpatho pathways Units Tables Tables Tables Tables Tables Tables Tables Tables Tables Tables Tables Tables

10. A Seventh Block administration Payments Reports consolidation Chasing Intellectual Property Rights Certification from Scientists Business Development issues Drafting agreements and signing

11. Data structuring Decide on Primary Key GI Number? Rv Number? For Drug Block? In the Brain storming session scientists elected to use Rv Number following TubercuList created by Stewart Cole’s group but also provide mapping to GI numbers

12. Anticipated Difficulties – Forced Redundancies Several drugs or small molecules for each protein Each drug has several attributes (Fields) Creation of Redundant entries – Records with repetition of Rv nos. Several immunochemical data for each protein antigen data Each study has different facets of immunochemical data Creation of Redundant entries – Records with repetition of Rv nos.

13. Another difficulty – Many published reports in the pre-genome sequence era did not use ORF nos. or ORF ids Mapping with calculated molecular weight is risky Due to (1) Experimental Errors? (2) Whether they were whole proteins or degraded or processed?

14. Caveats We will have a Redundant Database with replicate entries Each entry mapped to a singular PubMed ID is possible. In case of drugs, several PubMedIDs will come. We will never be able to use many data available in the literature

15. Result of a query Multiple data on some ORFs and little or no data on many ORFs Antigens Table Non-redundant Total

16. Post Genome era of M. tuberculosis Should experiments be repeated – If yes, then who will fund? If no, then how do we benefit?

17. We just have to live with it!

18. annot ABCPred BetaBarrelOuterMembraneProteins CDC1551HorizontalTransfer DNABinder DuplicatedGenes EssentialGene GeneFunctionPredictionOfIntergenicRegion InterdomInteractions InvariantSignatures Literature OperonMapTable Operons ORFFunctions OrthologousGenes PrintsPatterns PrositePatterns PsortSubcellularLocalisation RNABinder Rv2GI RvHorizontalTransfer UnfoldedandFolded 4 Basic questions to be pursued: How does a pathogen infect its host? How does latency arise? What is the process of infection? How pathogens are cleared by our immune system? IN OPEN SOURCE PORTAL (OPEN SOURCE DRUG DISCOVERY) USE R, BIOCONDUCTOR, WIKI/TWIKI drugs FirstLineDrugs FirstLineDrugsStructureActivity SecondLineDrugs DrugResistance NewDrugEntities DrugFailures DrugResponseRNAProtein TDRTargets

19. geneexpress MtbStrainWiseExpressionZScores CodonAdaptationIndex CodonAdaptationIndexCDC1551 CodonAdaptationIndexH37Ra ExperimentallyValidatedEssentialGenes GenesRequiredForOptimalGrowth GQuadraplexIntergenic3 GeneticComparison NonEssentialGenes GQuadraplexIntergenic GQuadraplexIntragenic1 Gquadraplexintragenic GQuadraplexRegulatory2 GQuadraplexRegulatory HighProbabilityOfEssentialGenes IntergenicRegionsHighExpressionGeneE IntergenicRegionsHighExpressionP miRNABindingSites 4 Basic questions to be pursued: How does a pathogen infect its host? How does latency arise? What is the process of infection? How pathogens are cleared by our immune system? IN OPEN SOURCE PORTAL (OPEN SOURCE DRUG DISCOVERY) USE R, BIOCONDUCTOR, WIKI/TWIKI hostpatho Antigens HostMimicry MtbPersistance SurfaceAdhesion VaccineCandidatesPad

20. 4 Basic questions to be pursued: How does a pathogen infect its host? How does latency arise? What is the process of infection? How pathogens are cleared by our immune system? pathways NewTransporter PathwayReaction STKinasesPhosphatases GenomeScaleMetabolicReactionNetwork IN OPEN SOURCE PORTAL (OPEN SOURCE DRUG DISCOVERY) USE R, BIOCONDUCTOR, WIKI/TWIKI strainpoly InDelintergenic InDelintragenic InterspersedRepetitive SNPintragenic SNPintergenic RvMIRUGenePosition TransposonMutantsFinal proteininteract ProteinInteraction ProteinProteinInteractionValues

24. Targeting Microbial Surface Proteins for therapeutics Attachment mediated by adhesins Colonization and pathogenesis FOUR CLASSES OF ADHESINS ARE KNOWN IN PATHOGENS Drug OR Antibody bind to adhesins and abrogate binding of pathogens to host cell receptors

25. All proteins of M. tuberculosis 3997 201 Give me proteins with Pad >= 0.7 15 How many proteins are in Antigens table? How many proteins have no match with Human proteins 57

27. Amit Sinha, Ayush Raman, Archana Pan, B.K.Malik, Balvinder Singh, Beena Pillai, Bhanot Priyamwada Sinha,Chabinath N. Mandal, Charu Kapil Richa, Chitra Dutta, Chitra Dutta, Debasis Dash, Debojyoti Chakraborty, Faraz Alam Ansari, G.P. Singh, Gajendra Pal Singh Raghava, Gargi Guhathakurta, Ipsita Chanda, Manoj Hariharan, Mekapati Bala Subramanyam, Mridula Bose, Mudgal Haymanti, Muthiah Gnanamani, Nanda Ghoshal, Pallavi Sarmah, Rakesh K. Sharma, Ranjan Basu, Ravishankar Ramachandran, Rupanjali Chaudhuri, Srinivasan Ramachandran*, Sabyasachi Das, Samir K. Brahmachari, Sandip Paul, Sanjib Chatterjee, Shantanu Chowdhury, Simone Gupta, Souvik Maiti, Subhagata Ghosh, Suchir Arora, Sudipto Saha, Sumit Deb, Vani Brahmachari, Vikram Kumar, Vinod Scaria, Yasha Bhasin, Yogendra Singh