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 IFNstimulated 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.is the most frequent cause of the common cold and has recently been recognized as the most frequent cause of exacerbations of asthma, a disease affecting ∼10% of the US population (1, 2). RV is also increasingly recognized to be a major cause of lung symptoms in patients with other chronic respiratory diseases and in young children (3). Previously, RV was thought to cause disease primarily in the nasal cavity, consistent with the observation that most RV strains replicate more robustly at the cooler temperatures found in the nasal cavity (33-35°C) than at lung temperature (37°C) (4, 5). However, the recent recognition that RV is an important cause of disease in the lung (2, 3) compels further investigation of the mechanisms that control the optimal replication temperature of this virus, which are unknown.Previous studies of the replication machinery of RV have not identified a virus-intrinsic reason for temperature-dependent growth, including studies of cell entry, uncoating, and polymerase activity (6, 7). Therefore, we considered the possibility that other factors, such as temperature-dependent host antiviral responses, might contribute to this phenotype. To investigate this possibility, we examined the effect of incubation temperature on the response to RV infection by the infected host cell. Using a mouse primary airway cell infection model, we observed that incubating cells at the lower temperature of the nasal cavity (33°C) greatly dim...

Short stem-loop RNAs activate RIG-I in mice, activating the innate immune system via specific patterns of gene expression.

Retinoic acid-inducible gene I (RIG-I) initiates a rapid innate immune response upon detection and binding to viral ribonucleic acid (RNA). This signal activation occurs only when pathogenic RNA is identified, despite the ability of RIG-I to bind endogenous RNA while surveying the cytoplasm. Here we show that ATP binding and hydrolysis by RIG-I play a key role in the identification of viral targets and the activation of signaling. Using biochemical and cell-based assays together with mutagenesis, we show that ATP binding, and not hydrolysis, is required for RIG-I signaling on viral RNA. However, we show that ATP hydrolysis does provide an important function by recycling RIG-I and promoting its dissociation from non-pathogenic RNA. This activity provides a valuable proof-reading mechanism that enhances specificity and prevents an antiviral response upon encounter with host RNA molecules.DOI: http://dx.doi.org/10.7554/eLife.09391.001