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Edited by Tadatsugu Taniguchi, University of Tokyo, Meguro-ku, Japan, and approved December 5, 2014 (received for review June 12, 2014)
Significance
Rhinovirus is the most frequent cause of the common cold, as well as one of the most important causes of asthma exacerbations. Most rhinovirus strains replicate better at the cooler temperatures found in the nasal cavity than at lung temperature, but the underlying mechanisms are not known. Using a mouse-adapted virus, we found that airway epithelial cells supporting rhinovirus replication initiate a more robust antiviral defense response through RIG-I–like receptor (RLR)–dependent interferon secretion and enhanced interferon responsiveness at lung temperature vs. nasal cavity temperature. Airway cells with genetic deficiencies in RLR or type I interferon receptor signaling supported much higher levels of viral replication at 37 °C. Thus, cooler temperatures can enable replication of the common cold virus, at least in part, by diminishing antiviral immune responses.
Abstract
Most isolates of human rhinovirus, the common cold virus, replicate more robustly at the cool temperatures found in the nasal cavity (33–35 °C) than at core body temperature (37 °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 °C vs. 37 °C. Mouse airway cells infected with mouse-adapted rhinovirus 1B exhibited a striking enrichment in expression of antiviral defense response genes at 37 °C relative to 33 °C, which correlated with significantly higher expression levels of type I and type III IFN genes and IFN-stimulated genes (ISGs) at 37 °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 °C relative to 33 °C at early time points poststimulation and to a sustained increase in the induction of ISGs at 37 °C relative to 33 °C. Recombinant type I IFN also stimulated more robust induction of ISGs at 37 °C than at 33 °C. Genetic deficiency of MAVS or the type I IFN receptor in infected airway cells permitted higher levels of viral replication, particularly at 37 °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.
Footnotes
↵1Present address: Jounce Therapeutics, Cambridge, MA 02138.
↵2Present address: Department of Ecology and Evolutionary Biology, Cornell University, Ithaca, NY 14853.
- ↵3To whom correspondence should be addressed. Email: akiko.iwasaki{at}yale.edu.
Author contributions: E.F.F., M.E.F., A.M.P., and A.I. designed research; E.F.F., J.A.S., M.E.F., and B.R.W. performed research; J.A.S., L.H., H.Z., and P.E.T. contributed new reagents/analytic tools; E.F.F., J.A.S., M.E.F., B.R.W., L.H., H.Z., P.E.T., A.M.P., and A.I. analyzed data; and E.F.F., M.E.F., A.M.P., and A.I. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The sequence of mouse-adapted rhinovirus 1B reported in this paper has been deposited in the GenBank database (accession no. KC881035), and the sequence of the parent rhinovirus 1B used in this study has also been deposited (accession no. KC881032).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1411030112/-/DCSupplemental.
Temperature-dependent innate control of rhinovirus
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