Conserved host response to highly pathogenic avian influenza virus infection in human cell culture, mouse and macaque model systems

Abstract

BackgroundUnderstanding host response to influenza virus infection will facilitate development of better diagnoses and therapeutic interventions. Several different experimental models have been used as a proxy for human infection, including cell cultures derived from human cells, mice, and non-human primates. Each of these systems has been studied extensively in isolation, but little effort has been directed toward systematically characterizing the conservation of host response on a global level beyond known immune signaling cascades.ResultsIn the present study, we employed a multivariate modeling approach to characterize and compare the transcriptional regulatory networks between these three model systems after infection with a highly pathogenic avian influenza virus of the H5N1 subtype. Using this approach we identified functions and pathways that display similar behavior and/or regulation including the well-studied impact on the interferon response and the inflammasome. Our results also suggest a primary response role for airway epithelial cells in initiating hypercytokinemia, which is thought to contribute to the pathogenesis of H5N1 viruses. We further demonstrate that we can use a transcriptional regulatory model from the human cell culture data to make highly accurate predictions about the behavior of important components of the innate immune system in tissues from whole organisms.ConclusionsThis is the first demonstration of a global regulatory network modeling conserved host response between in vitro and in vivo models.

2009 pandemic H1N1 influenza virus elicits similar clinical course but differential host transcriptional response in mouse, macaque, and swine infection models

“…Performing a comparative transcriptomic analysis across multiple model systems has revealed conserved responses during influenza infection, as demonstrated in a recent study by McDermott et al that used multivariate modeling approaches to identify similarities in transcriptional responses to H5N1 virus in the lungs of mice and macaques, and human lung epithelial cells [20]. To gain further insight into host responses to pH1N1 virus during acute infection, we examined lung gene expression from mice, macaques and swine infected with 2009 pandemic H1N1 influenza A/California/04/2009 (CA04) virus and compared the transcriptional response in each host.…”

A Semiautomated Framework for Integrating Expert Knowledge into Disease Marker Identification

“…A biological function-centric approach was used to determine the functionally enriched biological processes in the BALF and plasma samples of mice [32]. The biological processes are referred to the terms included in the biological process hierarchy in the GO.…”

“…The significantly changed proteins in the Ada −/− mice (relative to their controls) were mapped to their corresponding genes and compared with a list of all genes in the mouse genome in order to determine the levels of significance for individual biological processes in the data using a hypergeometric test. The GO terms with the enrichment P   values smaller than 10 −8 (in both BALF and plasma) were considered as significantly enriched biological processes in our data sets [32]. For each enriched GO term, we determined its own level (how specific the term is) and its top-level ancestor (broadest category that includes the term) within the biological process subontology.…”

Challenges in biomarker discovery: combining expert insights with statistical analysis of complex omics data

“…Pathway analysis approaches can also be used to compare differential expression of functional groups when individual genes may not be shared between two systems being compared. We have recently described one such approach in which significantly enriched functional groups in different systems were used to compare the responses of these systems to infection with influenza over time [75]. …”