Cell type- and replication stage-specific influenza virus responses in vivo

PLoS Pathog. 2020 Aug 13;16(8):e1008760. doi: 10.1371/journal.ppat.1008760. eCollection 2020 Aug.

Abstract

Influenza A viruses (IAVs) remain a significant global health burden. Activation of the innate immune response is important for controlling early virus replication and spread. It is unclear how early IAV replication events contribute to immune detection. Additionally, while many cell types in the lung can be infected, it is not known if all cell types contribute equally to establish the antiviral state in the host. Here, we use single-cycle influenza A viruses (scIAVs) to characterize the early immune response to IAV in vitro and in vivo. We found that the magnitude of virus replication contributes to antiviral gene expression within infected cells prior to the induction of a global response. We also developed a scIAV that is only capable of undergoing primary transcription, the earliest stage of virus replication. Using this tool, we uncovered replication stage-specific responses in vitro and in vivo. Using several innate immune receptor knockout cell lines, we identify RIG-I as the predominant antiviral detector of primary virus transcription and amplified replication in vitro. Through a Cre-inducible reporter mouse, we used scIAVs expressing Cre-recombinase to characterize cell type-specific responses in vivo. Individual cell types upregulate unique sets of antiviral genes in response to both primary virus transcription and amplified replication. We also identified antiviral genes that are only upregulated in response to direct infection. Altogether, these data offer insight into the early mechanisms of antiviral gene activation during influenza A infection.

Publication types

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

MeSH terms

  • A549 Cells
  • Animals
  • Antiviral Agents / pharmacology
  • DEAD Box Protein 58 / metabolism
  • Dogs
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology*
  • Epithelial Cells / virology
  • HEK293 Cells
  • Host-Pathogen Interactions / immunology*
  • Humans
  • Immunity, Innate / immunology*
  • Influenza A virus / drug effects
  • Influenza A virus / genetics
  • Influenza A virus / immunology*
  • Influenza A virus / isolation & purification
  • Influenza, Human / drug therapy
  • Influenza, Human / immunology*
  • Influenza, Human / pathology
  • Influenza, Human / virology
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mice, Inbred C57BL
  • Orthomyxoviridae Infections / drug therapy
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / virology
  • Receptors, Immunologic
  • Virus Replication*

Substances

  • Antiviral Agents
  • Receptors, Immunologic
  • DDX58 protein, human
  • DEAD Box Protein 58