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InnateDB: facilitating systems‐level analyses of the mammalian innate immune response

David J Lynn, Geoffrey L Winsor, Calvin Chan, Nicolas Richard, Matthew R Laird, Aaron Barsky, Jennifer L Gardy, Fiona M Roche, Timothy H W Chan, Naisha Shah, Raymond Lo, Misbah Naseer, Jaimmie Que, Melissa Yau, Michael Acab, Dan Tulpan, Matthew D Whiteside, Avinash Chikatamarla, Bernadette Mah, Tamara Munzner, Karsten Hokamp, Robert E W Hancock, Fiona S L Brinkman

Author Affiliations

  1. David J Lynn*,1,2,
  2. Geoffrey L Winsor1,
  3. Calvin Chan2,
  4. Nicolas Richard1,
  5. Matthew R Laird1,
  6. Aaron Barsky3,
  7. Jennifer L Gardy2,
  8. Fiona M Roche1,
  9. Timothy H W Chan2,
  10. Naisha Shah1,2,
  11. Raymond Lo1,
  12. Misbah Naseer2,
  13. Jaimmie Que2,
  14. Melissa Yau2,
  15. Michael Acab1,
  16. Dan Tulpan1,
  17. Matthew D Whiteside1,
  18. Avinash Chikatamarla2,
  19. Bernadette Mah2,
  20. Tamara Munzner3,
  21. Karsten Hokamp4,
  22. Robert E W Hancock2 and
  23. Fiona S L Brinkman*,1
  1. 1 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
  2. 2 Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada
  3. 3 Department of Computer Science, University of British Columbia, Vancouver, British Columbia, Canada
  4. 4 Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
  1. *Corresponding authors. Department of Molecular Bology and Biochemistry, Room SSB 8166, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, Canada V5A 1S6. Tel.: +778 782 2061; Fax: +778 782 5583; E-mail: dlynn{at}sfu.ca or Tel.: +778 782 5646; Fax: 778 782 5583; E-mail: brinkman{at}sfu.ca
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Abstract

Although considerable progress has been made in dissecting the signaling pathways involved in the innate immune response, it is now apparent that this response can no longer be productively thought of in terms of simple linear pathways. InnateDB (www.innatedb.ca) has been developed to facilitate systems‐level analyses that will provide better insight into the complex networks of pathways and interactions that govern the innate immune response. InnateDB is a publicly available, manually curated, integrative biology database of the human and mouse molecules, experimentally verified interactions and pathways involved in innate immunity, along with centralized annotation on the broader human and mouse interactomes. To date, more than 3500 innate immunity‐relevant interactions have been contextually annotated through the review of 1000 plus publications. Integrated into InnateDB are novel bioinformatics resources, including network visualization software, pathway analysis, orthologous interaction network construction and the ability to overlay user‐supplied gene expression data in an intuitively displayed molecular interaction network and pathway context, which will enable biologists without a computational background to explore their data in a more systems‐oriented manner.

Visual Overview

Synopsis

The importance of the innate immune response has long been recognized in the front line of defense against invading pathogens. If not tightly regulated, however, an overwhelming immune response can lead to what is sometimes called a cytokine storm. One such out‐of‐control response, sepsis, results in more than 200 000 deaths a year in the United States alone (Angus et al, 2001). Over the course of the last decade, significant progress has been made in understanding the innate immune response, including the detailed dissection of some of the critical signaling pathways involved (Lang and Mansell, 2007; Matsukawa, 2007). Despite these efforts, many questions remain unanswered including how the innate immune system initiates distinct responses toward particular pathogens. It is becoming increasingly clear that the innate immune response does not involve simple linear pathways but rather complex networks of pathways and interactions, positive and negative feedback loops and multifaceted transcriptional responses (Tegner et al, 2006; Lee and Kim, 2007). To better understand the complexities of the innate immune response and the cross‐talk between its components, complementary systems‐level analyses and more focused follow‐up experimental approaches are now needed.

Recently, researchers have started to apply systems biology approaches to the study of the immune system (Gilchrist et al, 2006; Tegner et al, 2006; Andersen et al, 2008) and bioinformatics resources are now emerging to aid these types of analyses. Despite the enormous efforts of the major publicly available interaction and pathway databases to provide as wide‐ranging cover as possible (Salwinski et al, 2004; Alfarano et al, 2005; Joshi‐Tope et al, 2005; Breitkreutz et al, 2007; Chatr‐aryamontri et al, 2007; Kanehisa et al, 2007; Kerrien et al, 2007), it was quickly apparent to us that currently available bioinformatics resources provided poor coverage and detail of the molecular interactions and pathways relevant to innate immunity, information that is essential for the systems‐orientated interpretation of large‐scale genomics data.

To overcome these problems and to provide a resource that will enable biologists without a computational background to explore their data in a more systems‐oriented manner, we have developed InnateDB. InnateDB (www.innatedb.ca) is a publicly available database and analysis platform for the genes, proteins, experimentally verified interactions and pathways involved in the human and murine innate immune responses.

One of the primary goals of InnateDB is to provide a manually curated centralized resource for experimentally verified human and mouse protein, gene and RNA molecular interactions involved in the innate immune system. To do this, a dedicated full‐time team of curators has been assembled to review the relevant biomedical literature and to submit detailed annotation on these interactions and pathways to InnateDB through customized submission system software. To date, more than 3500 innate immunity‐relevant interactions, involving around 1000 genes, have been manually curated through the review of approximately 1000 publications. Only interactions with published direct experimental evidence of a physical or biochemical interaction are submitted to InnateDB. The importance of manual curation is clear, as we are often able to double the number of interactions for a given gene or protein compared to the number currently present in the other interaction databases combined. Furthermore, this detailed manual curation permitted us to richly annotate these interactions and to place them in their relevant context. Interaction data in InnateDB are also curated, stored and downloadable in the Proteomics Standards Initiative Molecular Interaction (PSI‐MI) 2.5‐compliant XML format (Hermjakob et al, 2004).

In addition to the detailed manual curation of the genes, proteins and their interactions and pathways that are specifically known to have a role in the innate immune response, InnateDB also incorporates data on the entire human and mouse interactomes. To do this, annotation on more than 100 000 human and mouse interactions was integrated from several of the major publicly available interaction databases into InnateDB (Figure 1). To enable the investigation of genes, proteins and their molecular interactions that are relevant to particular pathways, InnateDB also includes cross‐references of genes not only to innate immunity‐relevant pathways but also to more than 2500 pathways from several of the major publicly available pathway databases (Figure 1). Detailed gene and protein annotation has also been extracted from a variety of other data sources.

Specific interactions, pathways and genes or proteins of interest can be interactively searched for in InnateDB through the flexible web‐based search interface of the database, providing a knowledge base for the community, whereas the bioinformatics and network visualization tools incorporated into InnateDB elevate the system from database to robust analysis platform. InnateDB allows one to integrate quantitative data (such as differential gene expression) into a molecular interaction network and pathway context, enabling the interrogation of such data in novel and insightful ways. Investigating differentially expressed molecular interaction networks may identify subnetworks or as‐yet unidentified pathways as being significantly involved in the response to a particular stimulus. By incorporating Cytoscape into InnateDB, investigators are able to take a closer look at the interactions involved in these pathways or subnetworks, potentially identifying cross‐talk between key pathways, and highlighting the molecules that are the hubs of these networks. Our Cerebral plugin allows one to further extend this experience, visually interrogating quantitative data across multiple conditions in more biologically intuitive pathway‐like layouts of networks, which are generated using subcellular localization information.

Integrated pathway over‐representation analysis can identify those pathways that are significantly associated with differentially regulated genes, highlighting those pathways that are significantly altered in their gene expression. Through such pathway analysis, it is possible to identify common pathways that are involved in the innate immune response to particular infections, and to identify the common central regulators of these pathways as attractive targets for immune modulation. (Figure 4).

InnateDB, along with other emerging resources for bioinformatics and systems‐level analysis of immunology (Kelley et al, 2005; Ortutay and Vihinen, 2006; Hijikata et al, 2007; Korb et al, 2008), will undoubtedly lead to novel and much deeper insights into the innate immune response to particular pathogens.

  • InnateDB is a molecular interaction and pathway database and analysis platform that has been developed to facilitate systems level analyses of the complex networks of pathways and interactions that govern the innate immune response, the wider immune system and the entire mammalian interactome.

  • To date, more than 3,500 innate immunity relevant interactions have been contextually annotated through the review of 1,000 plus publications.

  • Integrated into InnateDB are novel bioinformatics resources including, network visualization software, pathway analysis, orthologous interaction network construction and the ability to overlay user‐supplied gene expression data in an intuitively displayed molecular interaction network and pathway context, that will enable biologists without a computational background to explore their data in a more systems‐oriented, yet user‐friendly, manner.

Mol Syst Biol. 4: 218

  • Received May 21, 2008.
  • Accepted July 17, 2008.
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