Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 30, Pages 12117-12122Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1206039109
Keywords
microRNA; miR-142; small viral RNA
Categories
Funding
- National Institutes of Health [A1080624, A1093571, U19AI083025]
- National Institute of Allergy and Infectious Diseases (NIAID) Mucosal Immunity Study Team Program [U01AI095611]
- Center for Research on Influenza Pathogenesis, a NIAID-funded Centers of Excellence for Influenza Research and Surveillance Center for Research on Influenza Pathogenesis [HHSN266200700010C]
- New York University-Mount Sinai School of Medicine Mechanisms of Virus-Host Interactions National Institutes of Health [AI007647-09]
- Pew Charitable Trust
- Burroughs Wellcome Fund
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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.
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