Humans and other mammals are constantly exposed to a deluge of microorganisms, although they usually suffer little or no detrimental effects largely because microbes are efficiently dealt with in most cases by the host's immune system. Traditionally, the immune response has been divided into two different branches, the adaptive immune response and the innate immune response. In recent years, there has been an explosion of interest in the innate immune response. It is now appreciated that most pathogens to which we are exposed are eliminated through the innate immune response without necessarily requiring the activation of adaptive immunity. Furthermore, the importance of the innate immune response is being recognized in the initiation of and interplay with the adaptive immune response (MacLeod and Wetzler, 2007
), as well as the mechanism by which vaccine adjuvants operate in boosting immunity (Kwissa et al, 2007
). The innate immune response, however, can also be a double-edged sword. If not tightly regulated, 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
) and the discovery of several important pathogen recognition receptor families, such as the Toll-like receptors (TLRs) (Akira, 2006
), the nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs) (Inohara and Nunez, 2001
; Kanneganti et al, 2007
), and the retinoic acid-inducible gene 1 (RIG-1)-like receptors (RLRs) (Yoneyama et al, 2004
; Thompson and Locarnini, 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
; Oda and Kitano, 2006
; Tegner et al, 2006
; Andersen et al, 2008
) and bioinformatics resources are now emerging to aid these types of analyses. So far, these resources have tended to focus on particular aspects of genomics research; the Reference Database of Immune Cells (RefDIC), for example, provides transcriptomic and proteomic data from immune-relevant cells (Hijikata et al, 2007
), whereas others, such as the Innate Immunity Database, contain transcription profiles and computationally predicted transcription factor-binding sites for 2000 mouse immune genes (Korb et al, 2008
). Others still have been established primarily for a specific group of researchers, such as ImmPort (http://www.immport.org
), which has been created for researchers funded through the National Institute of Allergy and Infectious Diseases.
None of these resources provide detailed molecular interaction or pathway information and nor do they provide the capability to integrate disparate types of data to enable systems-level investigation of the immune response. Furthermore, 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 which is essential for the systems-orientated interpretation of large-scale genomics data. For example, TLR4, despite its status as one of the most important molecules in the innate immune response, has relatively few molecular interactions annotated in the major publicly available interaction databases. Five of these interaction databases combined contained annotated molecular interactions between TLR4 and just 11 other proteins. Through a review of the literature we have curated, in detail, a further 16 unique interactions, and provided annotation of nearly 60 different lines of evidence supporting these interactions.
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. InnateDB captures improved coverage of the innate immunity interactome by integrating more than 100 000 known interactions and approximately 2500 pathways from major public databases together with in-house manually curated data into a centralized resource. To date, the InnateDB curation team has reviewed more than 1000 publications and curated more than 3500 innate immunity-relevant interactions, richly annotating them in terms of the experimental evidence and the context in which they occur. Building on this data, several integrated bioinformatics and novel network visualization tools are provided to facilitate systems-level investigations of the innate immune response.
In particular, InnateDB facilitates the efficient analysis of large gene expression data sets in an interaction network and pathway context, allowing users to upload and integrate their own data that can then be interactively investigated. As a proof of concept, we have investigated the gene expression profiles of lipopolysaccharide (LPS)-stimulated THP-1 human monocytic cells at several time points. Using InnateDB, the expected significant involvement of the TNF-α and NF-κB pathways in the LPS response was identified, but InnateDB also provided deeper insight by probing the component molecular interactions involved.
By combining existing publicly available data on the general human and mouse interactomes with the manual curation of innate immune-relevant biomolecules and pathways, and by providing a user-friendly, accessible analysis environment, InnateDB provides a centralized integrative biology resource for researchers in immunology as well as the broader biomedical community.