the mycobacterium tuberculosis sysborg
DESCRIPTION
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. Life from the perspective of the pathogen. - PowerPoint PPT PresentationTRANSCRIPT
The Mycobacterium tuberculosis SysBorg
M. tuberculosis entering a macrophage
Latent stage
Infection process?
Latency?Im
mun
e cl
eara
nce?
Questions in Tuberculosis
Pi
Subvert Host signalling;
live within the enemy
Express antivirulence; Hide
Battle lost
Find surface receptors and enter; Friendship
Life from the perspective of the pathogen
N
Pathogen
GENOME
ORFs
PROTEIN SEQUENCES
SIMILARITY SEARCH ALGORITHMSBLAST, PLHoST, BLASTCLUST,…
FUNCTION PREDICTION BIOCHEMICAL ASSAYBIOPHYSICAL ASSAY
CLONING PROTEIN PRODUCED
TARGET SELECTION ALGORITHMSINVARIANT PEPTIDES, HIGH COST,
PATHOGEN(+) AND HUMAN(-), PDB, SURFACE PREDICTION
IN SILICO TARGET ASSESSMENTUSING M. tuberculosis SysBorg
FINALIZATION OF ORFs (CONSIDER EXPRESSION
ISSUES)
STEPS TO DRUG DISCOVERY
TARGET VALIDATION
Pathogen
GENOME
ORFs
PROTEIN SEQUENCES
SURFACE LOCALIZATION ALGORITHMSPSORT, SPAAN, MAAP,…
SURFACE PREDICTION
USE ANIMAL MODELS
CLONING PROTEIN PRODUCED
FILTERING ALGORITHMSEPITOPE PREDICTION, ALLERGENS,
ANTIGENIC REGIONS, TRANSMEMBRANE REGIONS PATHOGEN(+) AND HUMAN(-),
PDB
IN SILICO CANDIDATE ASSESSMENTUSING M. tuberculosis SysBorg
FINALIZATION OF ORFs (CONSIDER EXPRESSION
ISSUES)
STEPS TO VACCINE DISCOVERY
The Events
Chairman, proposes a networked initiative for tuberculosis
Co-ordinator assigned. Partnership with SilicoGene, Industry established
A first version of structure of SysBorg platform prepared. This had fixed number of Fields
A Brainstorming session was held
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
Scientists & students collect curated data in structured format
Data Plugged in to the platform
LINUX version also developed
Construction of M. tuberculosis SysBorg is a Mega Project
M. tuberculosis SysBorg
SKB DD
SC
SG
BKM
RR
CNM
BS
VB
MB
BP
YS
SR
RS
GPSR
RCHK
SM
BKM
Networking of expert scientists at the national level
M. tuberculosis SysBorg : A systems Biology platform for infectious diseases using Systems Biology of whole organism
( CSIR Task force Network for in silico drug target discovery )
VPCIACBR NII
IMTECH CDRI IICB RRLJOther partners
What does M.tb do during infection
How does Latency arise
How is the pathogen cleared
Y Y
FAD Fumarate
Coenzyme A
NADHATP
How does M.tb infect
Metabolic and Signalling Network
Activity structuring
annotation drugs geneexpress hostpatho strainpoly pathways
Units
Blocks
Tables
Tables
Tables
Tables Tables
Tables
Tables
Tables
Tables
Tables
Tables
Tables
A Seventh Block
administration
Payments Reports consolidation
Chasing Intellectual Property Rights
Business Development issues
Certification from Scientists
Drafting agreements and signing
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
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
Creation of Redundant entries – Records with repetition of Rv nos.
Each study has different facets of immunochemical data
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?
We will have a Redundant Database with replicate entries
Each entry mapped to a singular PubMed ID is possible. In case of drugs, several PubMed IDs will come.
We will never be able to use many data available in the literature
Caveats
Result of a query
Multiple data on some ORFs and little or no data on many ORFs
Antigens Table
Total Non-redundant
Post Genome era of M. tuberculosis
Should experiments be repeated –
If yes, then who will fund?If no, then how do we benefit?
We just have to live with it!
annot
ABCPredBetaBarrelOuterMembraneProteinsCDC1551HorizontalTransferDNABinderDuplicatedGenesEssentialGeneGeneFunctionPredictionOfIntergenicRegionInterdomInteractionsInvariantSignaturesLiteratureOperonMapTableOperonsORFFunctionsOrthologousGenesPrintsPatternsPrositePatternsPsortSubcellularLocalisationRNABinderRv2GIRvHorizontalTransferUnfoldedandFolded
IN OPEN SOURCE PORTAL (OPEN SOURCE DRUG DISCOVERY)
USE R, BIOCONDUCTOR, WIKI/TWIKI drugs
FirstLineDrugsFirstLineDrugsStructureActivity
SecondLineDrugsDrugResistance
NewDrugEntitiesDrugFailures
DrugResponseRNAProteinTDRTargets
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?
geneexpress
MtbStrainWiseExpressionZScoresCodonAdaptationIndexCodonAdaptationIndexCDC1551CodonAdaptationIndexH37RaExperimentallyValidatedEssentialGenesGenesRequiredForOptimalGrowthGQuadraplexIntergenic3
GeneticComparisonNonEssentialGenesGQuadraplexIntergenicGQuadraplexIntragenic1GquadraplexintragenicGQuadraplexRegulatory2GQuadraplexRegulatoryHighProbabilityOfEssentialGenesIntergenicRegionsHighExpressionGeneEIntergenicRegionsHighExpressionPmiRNABindingSites
IN OPEN SOURCE PORTAL (OPEN SOURCE DRUG DISCOVERY)
USE R, BIOCONDUCTOR, WIKI/TWIKI
hostpatho
AntigensHostMimicry
MtbPersistanceSurfaceAdhesion
VaccineCandidatesPad
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
pathways
NewTransporterPathwayReactionSTKinasesPhosphatasesGenomeScaleMetabolicReactionNetwork
proteininteract
ProteinInteractionProteinProteinInteractionValues
strainpoly
InDelintergenicInDelintragenic
InterspersedRepetitiveSNPintragenicSNPintergenic
RvMIRUGenePositionTransposonMutantsFinal
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?
Targeting Microbial Surface Proteins for therapeutics
Attachment mediated by adhesins
Colonization and pathogenesis
Drug OR Antibody bind to adhesins and abrogate binding of pathogens to host cell receptors
FOUR CLASSES OF ADHESINS ARE KNOWN IN PATHOGENS
All proteins of M. tuberculosis 3997
Give me proteins with Pad >= 0.7
201
How many proteins are in Antigens table?
15
How many proteins have no match with Human proteins
57
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