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Moving H5N1 studies into the era of systems biology.

ABSTRACT: The dynamics of H5N1 influenza virus pathogenesis are multifaceted and can be seen as an emergent property that cannot be comprehended without looking at the system as a whole. In past years, most of the high-throughput studies on H5N1-host interactions have focused on the host transcriptomic response, at the cellular or the lung tissue level. These studies pointed out that the dynamics and magnitude of the innate immune response and immune cell infiltration is critical to H5N1 pathogenesis. However, viral-host interactions are multidimensional and advances in technologies are creating new possibilities to systematically measure additional levels of 'omic data (e.g. proteomic, metabolomic, and RNA profiling) at each temporal and spatial scale (from the single cell to the organism) of the host response. Natural host genetic variation represents another dimension of the host response that determines pathogenesis. Systems biology models of H5N1 disease aim at understanding and predicting pathogenesis through integration of these different dimensions by using intensive computational modeling. In this review, we describe the importance of 'omic studies for providing a more comprehensive view of infection and mathematical models that are being developed to integrate these data. This review provides a roadmap for what needs to be done in the future and what computational strategies should be used to build a global model of H5N1 pathogenesis. It is time for systems biology of H5N1 pathogenesis to take center stage as the field moves toward a more comprehensive view of virus-host interactions.

SUBMITTER: Josset L

PROVIDER: S-EPMC3834220 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Moving H5N1 studies into the era of systems biology.

Josset Laurence L Tisoncik-Go Jennifer J Katze Michael G MG

Virus research 20130314 1

The dynamics of H5N1 influenza virus pathogenesis are multifaceted and can be seen as an emergent property that cannot be comprehended without looking at the system as a whole. In past years, most of the high-throughput studies on H5N1-host interactions have focused on the host transcriptomic response, at the cellular or the lung tissue level. These studies pointed out that the dynamics and magnitude of the innate immune response and immune cell infiltration is critical to H5N1 pathogenesis. How ...[more]

PMID: 23499671

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Project description:BackgroundPathway-oriented experimental and computational studies have led to a significant accumulation of biological knowledge concerning three major types of biological pathway events: molecular signaling events, gene regulation events, and metabolic reaction events. A pathway consists of a series of molecular pathway events that link molecular entities such as proteins, genes, and metabolites. There are approximately 300 biological pathway resources as of April 2009 according to the Pathguide database; however, these pathway databases generally have poor coverage or poor quality, and are difficult to integrate, due to syntactic-level and semantic-level data incompatibilities.ResultsWe developed the Human Pathway Database (HPD) by integrating heterogeneous human pathway data that are either curated at the NCI Pathway Interaction Database (PID), Reactome, BioCarta, KEGG or indexed from the Protein Lounge Web sites. Integration of pathway data at syntactic, semantic, and schematic levels was based on a unified pathway data model and data warehousing-based integration techniques. HPD provides a comprehensive online view that connects human proteins, genes, RNA transcripts, enzymes, signaling events, metabolic reaction events, and gene regulatory events. At the time of this writing HPD includes 999 human pathways and more than 59,341 human molecular entities. The HPD software provides both a user-friendly Web interface for online use and a robust relational database backend for advanced pathway querying. This pathway tool enables users to 1) search for human pathways from different resources by simply entering genes/proteins involved in pathways or words appearing in pathway names, 2) analyze pathway-protein association, 3) study pathway-pathway similarity, and 4) build integrated pathway networks. We demonstrated the usage and characteristics of the new HPD through three breast cancer case studies.ConclusionHPD http://bio.informatics.iupui.edu/HPD is a new resource for searching, managing, and studying human biological pathways. Users of HPD can search against large collections of human biological pathways, compare related pathways and their molecular entity compositions, and build high-quality, expanded-scope disease pathway models. The current HPD software can help users address a wide range of pathway-related questions in human disease biology studies.

Project description:BackgroundVaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood.Objective and methodsWe compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination.ResultsBoth vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination.ConclusionsUsing this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed.Trial registrationClinicalTrials.gov NCT01573312.

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Moving H5N1 studies into the era of systems biology.

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Moving H5N1 studies into the era of systems biology.

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