Reconstruction of the temporal signaling network in Salmonella-infected human cells

Salmonella enterica is a bacterial pathogen that usually infects its host through food sources. Translocation of the pathogen proteins into the host cells leads to changes in the signaling mechanism either by activating or inhibiting the host proteins. Using high-throughput ‘omic’ technologies, changes in the signaling components can be quantified at different levels; however, experimental hits are usually incomplete to represent the whole signaling system as some driver proteins stay hidden within the experimental data. Given that the bacterial infection modifies the response network of the host, more coherent view of the underlying biological processes and the signaling networks can be obtained by using a network modeling approach based on the reverse engineering principles in which a confident region from the protein interactome is found by inferring hits from the omic experiments. In this work, we have used a published temporal phosphoproteomic dataset of Salmonella-infected human cells and reconstructed the temporal signaling network of the human host by integrating the interactome and the phosphoproteomic datasets. We have combined two well-established network modeling frameworks, the Prize-collecting Steiner Forest (PCSF) approach and the Integer Linear Programming (ILP) based edge inference approach. The resulting network conserves the information on temporality, direction of interactions, while revealing hidden entities in the signaling, such as the SNARE binding, mTOR signaling, immune response, cytoskeleton organization, and apoptosis pathways. Targets of the Salmonella effectors in the host cells such as CDC42, RHOA, 14-3-3δ, Syntaxin family, Oxysterol-binding proteins were included in the reconstructed signaling network although they were not present in the initial phosphoproteomic data. We believe that integrated approaches have a high potential for the identification of clinical targets in infectious diseases, especially in the Salmonella infections

A Divide and Conquer Approach for Construction of Large-Scale Signaling Networks from PPI and RNAi Data Using Linear Programming

Inference of topology of signaling networks from perturbation experiments is a challenging problem. Recently, the inference problem has been formulated as a reference network editing problem and it has been shown that finding the minimum number of edit operations on a reference network to comply with perturbation experiments is an NP-complete problem. In this paper, we propose an integer linear optimization (ILP) model for reconstruction of signaling networks from RNAi data and a reference network. The ILP model guarantees the optimal solution; however, is practical only for small signaling networks of size 10-15 genes due to computational complexity. To scale for large signaling networks, we propose a divide and conquer-based heuristic, in which a given reference network is divided into smaller subnetworks that are solved separately and the solutions are merged together to form the solution for the large network. We validate our proposed approach on real and synthetic data sets, and comparison with the state of the art shows that our proposed approach is able to scale better for large networks while attaining similar or better biological accuracy

Construction of signaling pathways from PPI and RNAi data using Linear Programming

For the reconstruction of signaling pathways from RNAi data, an integer linear optimization model is proposed. The aim is to reconstruct the signaling network from the given protein protein interaction (PPI) network satisfying RNAi data by making minimum changes on the given network. For evaluation, 1000 reference PPI networks each with seven, eight, or nine proteins, and RNAi data for each of the regular proteins in the network were generated randomly. The solution was examined to have a general overview about reconstruction of signaling networks from RNAi data by using the proposed method