Two interferon-independent double-stranded RNA-induced host defense strategies suppress the common cold virus at warm temperature

Proc Natl Acad Sci U S A. 2016 Jul 26;113(30):8496-501. doi: 10.1073/pnas.1601942113. Epub 2016 Jul 11.


Most strains of rhinovirus (RV), the common cold virus, replicate better at cool temperatures found in the nasal cavity (33-35 °C) than at lung temperature (37 °C). Recent studies found that although 37 °C temperature suppressed RV growth largely by engaging the type 1 IFN response in infected epithelial cells, a significant temperature dependence to viral replication remained in cells devoid of IFN induction or signaling. To gain insight into IFN-independent mechanisms limiting RV replication at 37 °C, we studied RV infection in human bronchial epithelial cells and H1-HeLa cells. During the single replication cycle, RV exhibited temperature-dependent replication in both cell types in the absence of IFN induction. At 37 °C, earlier signs of apoptosis in RV-infected cells were accompanied by reduced virus production. Furthermore, apoptosis of epithelial cells was enhanced at 37 °C in response to diverse stimuli. Dynamic mathematical modeling and B cell lymphoma 2 (BCL2) overexpression revealed that temperature-dependent host cell death could partially account for the temperature-dependent growth observed during RV amplification, but also suggested additional mechanisms of virus control. In search of a redundant antiviral pathway, we identified a role for the RNA-degrading enzyme RNAseL. Simultaneous antagonism of apoptosis and RNAseL increased viral replication and dramatically reduced temperature dependence. These findings reveal two IFN-independent mechanisms active in innate defense against RV, and demonstrate that even in the absence of IFNs, temperature-dependent RV amplification is largely a result of host cell antiviral restriction mechanisms operating more effectively at 37 °C than at 33 °C.

Keywords: RNaseL; apoptosis; innate immunity; respiratory immunity; rhinovirus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • A549 Cells
  • Apoptosis / genetics
  • Bronchi / cytology
  • Cells, Cultured
  • Common Cold / virology
  • Epithelial Cells / metabolism
  • Epithelial Cells / virology
  • Gene Expression
  • HeLa Cells
  • Humans
  • Interferons / genetics*
  • Interferons / metabolism
  • RNA, Double-Stranded / genetics*
  • Respiratory Mucosa / cytology
  • Rhinovirus / genetics*
  • Rhinovirus / physiology
  • Temperature*
  • Virus Replication / genetics*


  • RNA, Double-Stranded
  • Interferons