Comparative analysis of anti-viral transcriptomics reveals novel effects of influenza immune antagonism.
BACKGROUND
Comparative analysis of genome-wide expression profiles are increasingly being used to study virus-specific host interactions. In order to gain mechanistic insights, gene expression profiles can be combined with information on DNA-binding sites of transcription factors to detect transcription factor activity (by analysis of target gene sets) during viral infections. Here, we apply this approach to study mechanisms of immune antagonism elicited by Influenza A virus (New Caledonia/20/1999) by comparing the transcriptional response with the non-pathogenic Newcastle disease virus (NDV), which lacks human immune antagonism.


RESULTS
Existing gene set approaches do not quantify activity in a way that can be statistically compared between responses. We thus developed a new method for Bayesian Estimation of Transcription factor Activity (BETA) that allows for such quantification and comparative analysis across multiple responses. BETA predicted decreased ISGF3 activity during influenza A infection of human dendritic cells (reflected in lower expression of Interferon Stimulated Genes, ISGs). This prediction was confirmed through a combination of mathematical modeling and experiments at different multiplicities of infection to show that ISGs were specifically blocked in infected cells. Suppression of the transcription factor SATB1 was also predicted as a novel effect of influenza-mediated immune antagonism, and validated experimentally.


CONCLUSIONS
Comparative analysis of genome-wide transcriptional profiles can reveal new effects of viral immune antagonism. We have developed a computational framework (BETA) that enables quantitative comparative analysis of transcription factor activities. This method will aid future studies to identify mechanistic differences in the host-pathogen interactions. Application of BETA to genome-wide transcriptional profiling data from human DCs identified SATB1 as a novel effect of influenza antagonism.
Department of Pathology, Yale School of Medicine, New Haven, CT, 06510, USA. juilee_thakar@urmc.rochester.edu.|Department of Microbiology and Immunology, University of Rochester, Rochester, NY, 14642, USA. juilee_thakar@urmc.rochester.edu.|Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY, 14642, USA. juilee_thakar@urmc.rochester.edu.
Juilee
J
Thakar
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. boris.hartmann@mssm.edu.|Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. boris.hartmann@mssm.edu.
Boris M
BM
Hartmann
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. nada.marjanovic@mssm.edu.
Nada
N
Marjanovic
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. stuart.sealfon@mssm.edu.|Center for Translational Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. stuart.sealfon@mssm.edu.
Stuart C
SC
Sealfon
Department of Pathology, Yale School of Medicine, New Haven, CT, 06510, USA. steven.kleinstein@yale.edu.|Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA. steven.kleinstein@yale.edu.
Steven H
SH
Kleinstein
D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects / Q000276:immunology*; D007251:Influenza, Human / Q000235:genetics* / Q000276:immunology*; D007372:Interferons / Q000494:pharmacology; D036961:Matrix Attachment Region Binding Proteins / Q000378:metabolism; D018448:Models, Immunological; D009522:Newcastle disease virus / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics*
D036961:Matrix Attachment Region Binding Proteins; D012333:RNA, Messenger; C076189:SATB1 protein, human; D014157:Transcription Factors; D007372:Interferons