title: Two interferon-independent double-stranded RNA-induced host defense strategies suppress the common cold virus at warm temperature.
abstract: 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.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Ellen F
authors.initials: EF
authors.lastname: Foxman
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: James A
authors.initials: JA
authors.lastname: Storer
authors.affiliation: Department of Biomedical Engineering, Systems Biology Institute, Yale University, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Kiran
authors.initials: K
authors.lastname: Vanaja
authors.affiliation: Department of Biomedical Engineering, Systems Biology Institute, Yale University, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Andre
authors.initials: A
authors.lastname: Levchenko
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; Howard Hughes Medical Institute, New Haven, CT 06520 akiko.iwasaki@yale.edu.
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwasaki
mesh_terms: D000072283:A549 Cells; D017209:Apoptosis / Q000235:genetics; D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D003139:Common Cold / Q000821:virology; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D007372:Interferons / Q000235:genetics* / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000235:genetics*; D020545:Respiratory Mucosa / Q000166:cytology; D012229:Rhinovirus / Q000235:genetics* / Q000502:physiology; D013696:Temperature; D014779:Virus Replication / Q000235:genetics*
chemical_list: D012330:RNA, Double-Stranded; D007372:Interferons
keywords: RNaseL; apoptosis; innate immunity; respiratory immunity; rhinovirus