DC-ATLAS: a systems biology resource to dissect receptor specific signal transduction in dendritic cells

Cavalieri et al. Immunome Research 2010, 6:10 http://www.immunome-research.com/content/6/1/10 IMMUNOME RESEARCH RESEARCH Open Access DC-ATLAS: a systems biology resource to dissect receptor specific signal transduction in dendritic cells Duccio Cavalieri1*, Damariz Rivero1, Luca Beltrame1, Sonja I Buschow2, Enrica Calura1,3, Lisa Rizzetto1, Sandra Gessani4, Maria C Gauzzi4, Walter Reith5, Andreas Baur6, Roberto Bonaiuti1, Marco Brandizi7, Carlotta De Filippo1, Ugo D’Oro8, Sorin Draghici9, Isabelle Dunand-Sauthier5, Evelina Gatti10, Francesca Granucci11, Michaela Gündel7, Matthijs Kramer12, Mirela Kuka8, Arpad Lanyi13, Cornelis JM Melief14, Nadine van Montfoort14, Renato Ostuni11, Philippe Pierre10, Razvan Popovici15, Eva Rajnavolgyi13, Stephan Schierer6, Gerold Schuler6, Vassili Soumelis16, Andrea Splendiani7, Irene Stefanini1, Maria G Torcia17, Ivan Zanoni11, Raphael Zollinger16, Carl G Figdor2, Jonathan M Austyn18 Abstract Background: The advent of Systems Biology has been accompanied by the blooming of pathway databases. Currently pathways are defined generically with respect to the organ or cell type where a reaction takes place. The cell type specificity of the reactions is the foundation of immunological research, and capturing this specificity is of paramount importance when using pathway-based analyses to decipher complex immunological datasets. Here, we present DC-ATLAS, a novel and versatile resource for the interpretation of high-throughput data generated perturbing the signaling network of dendritic cells (DCs). Results: Pathways are annotated using a novel data model, the Biological Connection Markup Language (BCML), a SBGN-compliant data format developed to store the large amount of information collected. The application of DCATLAS to pathway-based analysis of the transcriptional program of DCs stimulated with agonists of the toll-like receptor family allows an integrated description of the flow of information from the cellular sensors to the functional outcome, capturing the temporal series of activation events by grouping sets of reactions that occur at different time points in well-defined functional modules. Conclusions: The initiative significantly improves our understanding of DC biology and regulatory networks. Developing a systems biology approach for immune system holds the promise of translating knowledge on the immune system into more successful immunotherapy strategies. Background Dendritic cells (DCs) orchestrate a repertoire of immune responses that endow resistance to infections and tolerance to self. DC plasticity has a prominent role in eliciting the proper immune response. Different DC subsets display different receptors and surface molecules and express different sets of cytokines/chemokines, all of which lead to distinct immunological outcomes. Among the receptors are the innate pattern recognition * Correspondence: 1 Department of Pharmacology, University of Firenze, Firenze, Italy Full list of author information is available at the end of the article receptors (PRRs) that mediate the initial sensing of an infection. These include Toll-like receptors (TLRs), RIGI-like receptors (RLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs) [1]. TLRs recognize conserved structures of microbes and are localized on the cell surface (TLR1, TLR2, TLR4, TLR5 and TLR6) to recognize bacterial and fungal cell wall components or in intracellular membranes such as endosomes or phagosomes (TLR3, TLR7, TLR8 and TLR9) where they recognize viral or microbial nucleic acids [1]. Thus, different TLRs are amenable to targeting by different types of agents [2]. © 2010 Cavalieri et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cavalieri et al. Immunome Research 2010, 6:10 http://www.immunome-research.com/content/6/1/10 Because of their essential role in the initiation of an adaptive immune response, DCs are an attractive target for therapeutic manipulation of the immune system [3]. In fact, DC physiology is one of the research areas where basic knowledge has been more readily translated into clinical applications. DC-based vaccines have been rapidly transferred from the laboratory to the clinic. However, it is evident that, after more than ten years of worldwide experience with DC vaccination, the therapeutic potential of these cells has not yet been entirely exploited [4]. We thus need to improve our understanding of the complex biology of these cells [5] that operate at the crossroad of innate and adaptive immunity. The complexity and heterogeneity of the DC system however, may require a shift from reductionism to more holistic systems biology approaches. We expect that more detailed insight in the signaling pathways that operate in DCs will open new perspectives for a better exploitation of their therapeutic potential. Immune systems biology is defined as the comprehensive and quantitative study of interactions between hosts and microbes over time, leading to the generation of models describing their dynamic behavior of immune cells and pathogens. Many studies investigated immune cell since these cells are particularly suited to functional genomics analyses because their responses to specific stimuli in a controlled environment can be clearly categorized. Innate responses against pathogens however cannot be considered as a set of discrete signaling pathways activated by a pathogen binding to a receptor; but rather such responses are composed of many interconnected pathways depending on multiple factors. Important initiatives based on systems biology are arising to collect high throughput data and to develop sophisticated bioinformatic methods to compare and analyze these data. In this respect, the Immunological Genome Project initiative [6] represents the first transcriptomic project to apply a truly systems-level approach to the analysis of immune cell populations. Current publicly available pathway databases provide generic rather than thematic or cell-type specific pathways. Nevertheless, certain initiatives are proposing the cellular specificity of certain reactions. In recent studies [7] a comprehensive map of macrophage molecular interactions was created, including ligands such as PAMPs and interleukins as input signals, and the release of cytokines and lipids as output signals. Recently a macrophage specific pathways database valuable for computational modeling and for the interpretation of functional genomics data has been published [8]. At the time of writing, initiatives aiming at a better description of the signaling networks of DCs are underway [9]. Page 2 of 12 Here we describe DC-ATLAS, a collection of pathways specifically curated in DC, that can be exploited, (...truncated)