Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

Ryan A. Langlois, Andrew Varble, Mark A. Chua, Adolfo García-Sastre, Benjamin R. TenOever

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

A coordinated innate and adaptive immune response, orchestrated by antigen presenting cells (APCs), is required for effective clearance of influenza A virus (IAV). Although IAV primarily infects epithelial cells of the upper respiratory tract, APCs are also susceptible. To determine if virus transcription in these cells is required to generate protective innate and adaptive immune responses, we engineered IAV to be selectively attenuated in cells of hematopoietic origin. Incorporation of hematopoietic-specific miR-142 target sites into the nucleoprotein of IAV effectively silenced virus transcription in APCs, but had no significant impact in lung epithelial cells. Here we demonstrate that inhibiting IAV replication in APCs in vivo did not alter clearance, or the generation of IAV-specific CD8 T cells, suggesting that cross-presentation is sufficient for cytotoxic T lymphocyte activation. In contrast, loss of in vivo virus infection, selectively in APCs, resulted in a significant reduction of retinoic acid-inducible gene I-dependent type I IFN (IFN-I). These data implicate the formation of virus replication intermediates in APCs as the predominant trigger of IFN-I in vivo. Taking these data together, this research describes a unique platform to study the host response to IAV and provides insights into the mechanism of antigen presentation and the induction of IFN-I.

Original languageEnglish (US)
Pages (from-to)12117-12122
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number30
DOIs
StatePublished - Jul 24 2012

Keywords

  • MicroRNA
  • Small viral RNA
  • miR-142

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