1. Cytokine systems approach demonstrates differences in innate and pro-inflammatory host responses between genetically distinct MERS-CoV isolates
- Author
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Jean Chang, Michael G. Katze, Vineet D. Menachery, Christian Selinger, Sara M. Kelly, G. Lynn Law, Sudhakar Agnihothram, Ralph S. Baric, Jennifer Tisoncik-Go, Pavel Sova, Department of Microbiology, University of Washington, University of Washington [Seattle]-Departement of Microbiology, University of North Carolina at Chapel Hill School of Medicine, University of North Carolina [Chapel Hill] (UNC), and University of North Carolina System (UNC)-University of North Carolina System (UNC)
- Subjects
STAT3 Transcription Factor ,Time Factors ,Middle East respiratory syndrome coronavirus ,viruses ,Biology ,medicine.disease_cause ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,Computational topology ,Cell Line ,MERS-CoV ,Cytokine simulation ,Immunity ,Gene expression ,medicine ,Genetics ,Humans ,Transcriptomics ,Gene ,ComputingMilieux_MISCELLANEOUS ,Coronavirus ,Inflammation ,Innate immune system ,Gene Expression Profiling ,virus diseases ,Genomics ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Immunity, Innate ,3. Good health ,respiratory tract diseases ,Gene expression profiling ,Immunology ,Host-Pathogen Interactions ,Middle East Respiratory Syndrome Coronavirus ,Middle East respiratory syndrome ,Cytokines ,Biotechnology ,Research Article - Abstract
Background The recent emergence of a novel coronavirus in the Middle East (designated MERS-CoV) is a reminder of the zoonotic and pathogenic potential of emerging coronaviruses in humans. Clinical features of Middle East respiratory syndrome (MERS) include atypical pneumonia and progressive respiratory failure that is highly reminiscent of severe acute respiratory syndrome (SARS) caused by SARS-CoV. The host response is a key component of highly pathogenic respiratory virus infection. Here, we computationally analyzed gene expression changes in a human airway epithelial cell line infected with two genetically distinct MERS-CoV strains obtained from human patients, MERS-CoV SA 1 and MERS-CoV Eng 1. Results Using topological techniques, including persistence homology and filtered clustering, we performed a comparative transcriptional analysis of human Calu-3 cell host responses to the different MERS-CoV strains, with MERS-CoV Eng 1 inducing early kinetic changes, between 3 and 12 hours post infection, compared to MERS-CoV SA 1. Robust transcriptional changes distinguished the two MERS-CoV strains predominantly at the late time points. Combining statistical analysis of infection and cytokine-stimulated Calu-3 transcriptomics, we identified differential innate responses, including up-regulation of extracellular remodeling genes following MERS-CoV Eng 1 infection and differential pro-inflammatory responses. Conclusions Through our genomics-based approach, we found topological differences in the kinetics and magnitude of the host response to MERS-CoV SA 1 and MERS-CoV Eng 1, with differential expression of innate immune and pro-inflammatory responsive genes as a result of IFN, TNF and IL-1α signaling. Predicted activation for STAT3 mediating gene expression relevant for epithelial cell-to-cell adherens and junction signaling in MERS-CoV Eng 1 infection suggest that these transcriptional differences may be the result of amino acid differences in viral proteins known to modulate innate immunity during MERS-CoV infection. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-1161) contains supplementary material, which is available to authorized users.
- Published
- 2014
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