Giuseppe
Emeritus
[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]
Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses
Ryan A. Langlois<SUP>a</SUP>, Andrew Varble<SUP>a</SUP>, Mark A. Chua<SUP>a</SUP>, Adolfo Garc?a-Sastre<SUP>a</SUP>,<SUP>b</SUP>, and Benjamin R. tenOever<SUP>a</SUP>,<SUP>1</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Department of Microbiology and Global Health and Emerging Pathogens Institute, and <SUP>b</SUP>Division of Infectious Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029
Edited by Dan R. Littman, New York University Medical Center, New York, NY, and approved June 15, 2012 (received for review April 10, 2012)
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.
Footnotes
- ------Ryan A. Langlois<SUP>a</SUP>, Andrew Varble<SUP>a</SUP>, Mark A. Chua<SUP>a</SUP>, Adolfo Garc?a-Sastre<SUP>a</SUP>,<SUP>b</SUP>, and Benjamin R. tenOever<SUP>a</SUP>,<SUP>1</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Department of Microbiology and Global Health and Emerging Pathogens Institute, and <SUP>b</SUP>Division of Infectious Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029
Edited by Dan R. Littman, New York University Medical Center, New York, NY, and approved June 15, 2012 (received for review April 10, 2012)
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.
Footnotes
- ↵<SUP>1</SUP>To whom correspondence should be addressed. E-mail: Benjamin.tenOever@mssm.edu.
- Author contributions: R.A.L. and B.R.t. designed research; R.A.L., A.V., and M.A.C. performed research; A.V. and A.G.-S. contributed new reagents/analytic tools; R.A.L. analyzed data; and R.A.L. and B.R.t. wrote the paper.
- The authors declare no conflict of interest.
- This article is a PNAS Direct Submission.
- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1206039109/-/DCSupplemental.