Curating the innate immunity interactome

Abstract

BackgroundThe innate immune response is the first line of defence against invading pathogens and is regulated by complex signalling and transcriptional networks. Systems biology approaches promise to shed new light on the regulation of innate immunity through the analysis and modelling of these networks. A key initial step in this process is the contextual cataloguing of the components of this system and the molecular interactions that comprise these networks. InnateDB (http://www.innatedb.com) is a molecular interaction and pathway database developed to facilitate systems-level analyses of innate immunity.ResultsHere, we describe the InnateDB curation project, which is manually annotating the human and mouse innate immunity interactome in rich contextual detail, and present our novel curation software system, which has been developed to ensure interactions are curated in a highly accurate and data-standards compliant manner. To date, over 13,000 interactions (protein, DNA and RNA) have been curated from the biomedical literature. Here, we present data, illustrating how InnateDB curation of the innate immunity interactome has greatly enhanced network and pathway annotation available for systems-level analysis and discuss the challenges that face such curation efforts. Significantly, we provide several lines of evidence that analysis of the innate immunity interactome has the potential to identify novel signalling, transcriptional and post-transcriptional regulators of innate immunity. Additionally, these analyses also provide insight into the cross-talk between innate immunity pathways and other biological processes, such as adaptive immunity, cancer and diabetes, and intriguingly, suggests links to other pathways, which as yet, have not been implicated in the innate immune response.ConclusionsIn summary, curation of the InnateDB interactome provides a wealth of information to enable systems-level analysis of innate immunity.

The NRF2‐related interactome and regulome contain multifunctional proteins and fine‐tuned autoregulatory loops

“…SKN-1 was found to be involved in oocyte maturation [29], while NRF2 have recently been described to take part in spermatogenesis [30], suggesting the importance of NRF2 in reproduction; however, reproduction is not yet among the GO annotations of NRF2. Similarly, immune-related processes are also missing from the GO annotations of NRF2 though 32% of the NRF2 interactors have immune functions and NRF2 is known to be involved in innate immunity [16]. We and others recently proved the role of SKN-1 in the pathogen response of C. elegans suggesting a high-level functional similarity between NRF2 and SKN-1 [31,32].…”

“…While there are more than 2300 articles for the keyword 'NRF2' in PubMed (as of January 2012), major protein-protein interaction resources (BioGRID, MINT, STRING, HPRD) contain only a few (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) interactors for NRF2. Besides one study on the global mapping of binding sites for NRF2 through ChIP-Seq profiling [10] and a specific network modeling approach on Nrf2 regulation in mouse lung [11], there is no large-scale collection of NRF2-regulated target genes.…”

Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes

“…All connections are supported by published data stored in the Ingenuity Pathways Knowledge Base and/or PubMed 33 . Pathway enrichment analysis of differentially expressed genes, clusters of cocorrelated genes and eQTL genes was performed using InnateDB 34 .…”

Atypical Activation of the Unfolded Protein Response in Cystic Fibrosis Airway Cells Contributes to p38 MAPK-Mediated Innate Immune Responses

“…Briefly, a list of protein-level interactions between DE genes (FC . 61.4; p , 0.05) was obtained using InnateDB (32). Network analysis was carried out by visualizing these interactions into a single integrated network using Cytoscape (2.8.0 for Windows) and the software plugin Cerebral to appreciate cellular directionality, as previously described (33).…”