Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 3, Pages 827-832Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1411030112
Keywords
rhinovirus; common cold; airway; RIG-I; innate immunity
Categories
Funding
- NIH [AI054359S1, T32 HL007974, AI054359, AI064705, UL1 TR000142]
- NIH Training Grant [2T32AI007640]
- NIH/National Institute of Allergy and Infectious Diseases [U54AI057160]
- National Science Foundation [DEB-1021243]
- Division Of Environmental Biology
- Direct For Biological Sciences [1051093] Funding Source: National Science Foundation
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Most isolates of human rhinovirus, the common cold virus, replicate more robustly at the cool temperatures found in the nasal cavity (33-35 degrees C) than at core body temperature (37 degrees C). To gain insight into the mechanism of temperature-dependent growth, we compared the transcriptional response of primary mouse airway epithelial cells infected with rhinovirus at 33 degrees C vs. 37 degrees C. Mouse airway cells infected with mouse-adapted rhinovirus 1B exhibited a striking enrichment in expression of antiviral defense response genes at 37 degrees C relative to 33 degrees C, which correlated with significantly higher expression levels of type I and type III IFN genes and IFN-stimulated genes (ISGs) at 37 degrees C. Temperature-dependent IFN induction in response to rhinovirus was dependent on the MAVS protein, a key signaling adaptor of the RIG-I-like receptors (RLRs). Stimulation of primary airway cells with the synthetic RLR ligand poly I: C led to greater IFN induction at 37 degrees C relative to 33 degrees C at early time points poststimulation and to a sustained increase in the induction of ISGs at 37 degrees C relative to 33 degrees C. Recombinant type I IFN also stimulated more robust induction of ISGs at 37 degrees C than at 33 degrees C. Genetic deficiency of MAVS or the type I IFN receptor in infected airway cells permitted higher levels of viral replication, particularly at 37 degrees C, and partially rescued the temperature-dependent growth phenotype. These findings demonstrate that in mouse airway cells, rhinovirus replicates preferentially at nasal cavity temperature due, in part, to a less efficient antiviral defense response of infected cells at cool temperature.
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