title: Cytokine systems approach demonstrates differences in innate and pro-inflammatory host responses between genetically distinct MERS-CoV isolates.
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.
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA. csel@uw.edu.
authors.forename: Christian
authors.initials: C
authors.lastname: Selinger
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA. tisoncik@uw.edu.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tisoncik-Go
authors.affiliation: Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA. vineet@email.unc.edu.
authors.forename: Vineet D
authors.initials: VD
authors.lastname: Menachery
authors.affiliation: Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA. agniss@email.unc.edu.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Agnihothram
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA. gllaw@uw.edu.
authors.forename: G Lynn
authors.initials: GL
authors.lastname: Law
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA. mspiggy1@uw.edu.
authors.forename: Jean
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA. smkelly@uw.edu.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Kelly
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA. ps44@uw.edu.
authors.forename: Pavel
authors.initials: P
authors.lastname: Sova
authors.affiliation: Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA. rbaric@email.unc.edu.
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Baric
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA. honey@uw.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
mesh_terms: D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D020869:Gene Expression Profiling; D023281:Genomics; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000821:virology; D065207:Middle East Respiratory Syndrome Coronavirus / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013997:Time Factors
chemical_list: D016207:Cytokines; D050796:STAT3 Transcription Factor