Inferring a protein interaction map of Mycobacterium tuberculosis based on sequences and interologs

Background: Mycobacterium tuberculosis is an infectious bacterium posing serious threats to human health. Due to the difficulty in performing molecular biology experiments to detect protein interactions, reconstruction of a protein interaction map of M. tuberculosis by computational methods will provide crucial information to understand the biological processes in the pathogenic microorganism, as well as provide the framework upon which new therapeutic approaches can be developed.Results: In this paper, we constructed an integrated M. tuberculosis protein interaction network by machine learning and ortholog-based methods. Firstly, we built a support vector machine (SVM) method to infer the protein interactions of M. tuberculosis H37Rv by gene sequence information. We tested our predictors in Escherichia coli and mapped the genetic codon features underlying its protein interactions to M. tuberculosis. Moreover, the documented interactions of 14 other species were mapped to the interactome of M. tuberculosis by the interolog method. The ensemble protein interactions were validated by various functional relationships, i.e., gene coexpression, evolutionary relationship and functional similarity, extracted from heterogeneous data sources. The accuracy and validation demonstrate the effectiveness and efficiency of our framework.Conclusions: A protein interaction map of M. tuberculosis is inferred from genetic codons and interologs. The prediction accuracy and numerically experimental validation demonstrate the effectiveness and efficiency of our method. Furthermore, our methods can be straightforwardly extended to infer the protein interactions of other bacterial species. © 2012 Liu et al.; licensee BioMed Central Ltd.Link_to_subscribed_fulltex

Network generation and analysis for the investigation of host-pathogen interactions in tuberculosis Holifidy Arisoa Rapanoel.

Scroll down to electronic link to access the thesis.Includes abstract.Includes bibliographical references.This project aims to predict protein interactions between human and Mtb. The interologs method based on experimentally verified intra-species and inter-species interactions was used to predict human-Mtb protein interactions. They were further filtered using known host-pathogen interactions and genes that are differentially expressed during infection. This yielded a total of 190 interactions. Analysis of the subcellular location of the human-Mtb interactions showed that they are potentially feasible. The biological processes of the predicted human proteins suggested their involvement in apoptosis and production of nitric oxide, whereas those of the Mtb proteins were relevant to the intracellular environment of Mtb in the host

Predicting and analyzing interactions between Mycobacterium tuberculosis and its human host

The outcome of infection by Mycobacterium tuberculosis (Mtb) depends greatly on how the host responds to the bacteria and how the bacteria manipulates the host, which is facilitated by protein-protein interactions. Thus, to understand this process, there is a need for elucidating protein interactions between human and Mtb, which may enable us to characterize specific molecular mechanisms allowing the bacteria to persist and survive under different environmental conditions. In this work, we used the interologs method based on experimentally verified intra-species and inter-species interactions to predict human-Mtb functional interactions. These interactions were further filtered using known human-Mtb interactions and genes that are differentially expressed during infection, producing 190 interactions. Further analysis of the subcellular location of proteins involved in these human-Mtb interactions confirms feasibility of these interactions. We also conducted functional analysis of human and Mtb proteins involved in these interactions, checking whether these proteins play a role in infection and/or disease, and enriching Mtb proteins in a previously predicted list of drug targets. We found that the biological processes of the human interacting proteins suggested their involvement in apoptosis and production of nitric oxide, whereas those of the Mtb interacting proteins were relevant to the intracellular environment of Mtb in the host. Mapping these proteins onto KEGG pathways highlighted proteins belonging to the tuberculosis pathway and also suggested that Mtb proteins might use the host to acquire nutrients, which is in agreement with the intracellular lifestyle of Mtb. This indicates that these interactions can shed light on the interplay between Mtb and its human host and thus, contribute to the process of designing novel drugs with new biological mechanisms of action

Mycobacterium tuberculosis and Clostridium difficille interactomes: demonstration of rapid development of computational system for bacterial interactome prediction

Background\ud Protein-protein interaction (PPI) networks (interactomes) of most organisms, except for some model organisms, are largely unknown. Experimental methods including high-throughput techniques are highly resource intensive. Therefore, computational discovery of PPIs can accelerate biological discovery by presenting "most-promising" pairs of proteins that are likely to interact. For many bacteria, genome sequence, and thereby genomic context of proteomes, is readily available; additionally, for some of these proteomes, localization and functional annotations are also available, but interactomes are not available. We present here a method for rapid development of computational system to predict interactome of bacterial proteomes. While other studies have presented methods to transfer interologs across species, here, we propose transfer of computational models to benefit from cross-species annotations, thereby predicting many more novel interactions even in the absence of interologs. Mycobacterium tuberculosis (Mtb) and Clostridium difficile (CD) have been used to demonstrate the work.\ud \ud Results\ud We developed a random forest classifier over features derived from Gene Ontology annotations and genetic context scores provided by STRING database for predicting Mtb and CD interactions independently. The Mtb classifier gave a precision of 94% and a recall of 23% on a held out test set. The Mtb model was then run on all the 8 million protein pairs of the Mtb proteome, resulting in 708 new interactions (at 94% expected precision) or 1,595 new interactions at 80% expected precision. The CD classifier gave a precision of 90% and a recall of 16% on a held out test set. The CD model was run on all the 8 million protein pairs of the CD proteome, resulting in 143 new interactions (at 90% expected precision) or 580 new interactions (at 80% expected precision). We also compared the overlap of predictions of our method with STRING database interactions for CD and Mtb and also with interactions identified recently by a bacterial 2-hybrid system for Mtb. To demonstrate the utility of transfer of computational models, we made use of the developed Mtb model and used it to predict CD protein-pairs. The cross species model thus developed yielded a precision of 88% at a recall of 8%. To demonstrate transfer of features from other organisms in the absence of feature-based and interaction-based information, we transferred missing feature values from Mtb orthologs into the CD data. In transferring this data from orthologs (not interologs), we showed that a large number of interactions can be predicted.\ud \ud Conclusions\ud Rapid discovery of (partial) bacterial interactome can be made by using existing set of GO and STRING features associated with the organisms. We can make use of cross-species interactome development, when there are not even sufficient known interactions to develop a computational prediction system. Computational model of well-studied organism(s) can be employed to make the initial interactome prediction for the target organism. We have also demonstrated successfully, that annotations can be transferred from orthologs in well-studied organisms enabling accurate predictions for organisms with no annotations. These approaches can serve as building blocks to address the challenges associated with feature coverage, missing interactions towards rapid interactome discovery for bacterial organisms.\ud \ud Availability\ud The predictions for all Mtb and CD proteins are made available at: http://severus.dbmi.pitt.edu/TB and http://severus.dbmi.pitt.edu/CD respectively for browsing as well as for download

An integrative approach to studying protein-protein interactions within the genome of Mycobacterium tuberculosis

Includes bibliographical references (leaves 96-103).Proteins mediate bio-chemical processes in cellular organisms by functioning as structural components, signaling molecules, enzymes, transcription factors and receptors, through complex interactions that they make with one another. The study of protein-protein interactions (PPI) within an organism is thus a vital step towards understanding the cellular life process of an organism. PPIs have been studied by specially designed experiments to identify pairs of proteins that are suspected to interact. Experimental approaches are quite expensive, yet still there are cases of wrongly identified protein-protein interactions. In this study, we predict PPIs computationally by exploiting known properties of proteins and PPIs and the requirement that proteins be present in the same cell compartment at the same time in order to interact (subcellular localization and gene expression)

Computational Network Inference for Bacterial Interactomics

Since the large-scale experimental characterization of protein–protein interactions (PPIs) is not possible for all species, several computational PPI prediction methods have been developed that harness existing data from other species. While PPI network prediction has been extensively used in eukaryotes, microbial network inference has lagged behind. Since the large-scale experimental characterization of protein–protein interactions (PPIs) is not possible for all species, several computational PPI prediction methods have been developed that harness existing data from other species. While PPI network prediction has been extensively used in eukaryotes, microbial network inference has lagged behind. However, bacterial interactomes can be built using the same principles and techniques; in fact, several methods are better suited to bacterial genomes. These predicted networks allow systems-level analyses in species that lack experimental interaction data. This review describes the current network inference and analysis techniques and summarizes the use of computationally-predicted microbial interactomes to date