Distinct antiviral signatures revealed by the magnitude and round of influenza virus replication in vivo

Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):9610-9615. doi: 10.1073/pnas.1807516115. Epub 2018 Sep 4.

Abstract

Influenza virus has a broad cellular tropism in the respiratory tract. Infected epithelial cells sense the infection and initiate an antiviral response. To define the antiviral response at the earliest stages of infection we used a series of single-cycle reporter viruses. These viral probes demonstrated cells in vivo harbor a range in magnitude of virus replication. Transcriptional profiling of cells supporting different levels of replication revealed tiers of IFN-stimulated gene expression. Uninfected cells and cells with blunted replication expressed a distinct and potentially protective antiviral signature, while cells with high replication expressed a unique reserve set of antiviral genes. Finally, we used these single-cycle reporter viruses to determine the antiviral landscape during virus spread, which unveiled disparate protection of epithelial cell subsets mediated by IFN in vivo. Together these results highlight the complexity of virus-host interactions within the infected lung and suggest that magnitude and round of replication tune the antiviral response.

Keywords: influenza virus; interferon-stimulated gene; viral tropism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dogs
  • Epithelial Cells / immunology
  • Epithelial Cells / virology
  • Gene Expression Profiling / methods
  • HEK293 Cells
  • High-Throughput Nucleotide Sequencing
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Influenza A virus / isolation & purification
  • Influenza A virus / physiology*
  • Influenza, Human / immunology
  • Influenza, Human / pathology
  • Influenza, Human / virology*
  • Interferons / immunology
  • Lung / cytology
  • Lung / immunology
  • Lung / pathology
  • Lung / virology*
  • Madin Darby Canine Kidney Cells
  • Mice, Inbred C57BL
  • RNA, Viral / isolation & purification
  • Sequence Analysis, DNA
  • Virus Replication / immunology*

Substances

  • RNA, Viral
  • Interferons