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. apoptosis | RNaseL | innate immunity | rhinovirus | respiratory immunity I n the 1960s, rhinoviruses (RVs) were first cultured from patient samples and shown to cause acute upper respiratory infections (a.k.a. common colds). Early work showed that RV isolates replicated best in culture when incubated at temperatures slightly cooler than core body temperature (33-35°C) (1, 2). This observation fit with the role of RV as a cause of disease in the nasal cavity, but not the lungs, as the nasal cavity is cooled by inhalation of environmental air, but the lungs are generally considered to be at core body temperature (37°C). The primary target cells of RV infection are the airway epithelial cells that line the respiratory tract. Similar to all cells of the body, airway epithelial cells are equipped with a cell-intrinsic innate immune system that can sense the presence of a viral infection, using pattern recognition receptors such as toll-like receptors (TLRs) and RIG-I like receptors (RLRs), and can respond to the infection by inducing antiviral effector mechanisms (3). Recently, we used mouse primary airway cells and a mouse-adapted RV to show that replicating RV is recognized by the RLRs within airway epithelial cells, leading to two innate immune signaling events that occur more robustly at warm temperature than at cool temperatu...

Early local immune defences in the respiratory tract

“…Therefore the characteristics of the inhaled air, including its temperature, can potentially impact the biology of the surface epithelium. Changing the ambient temperature of AECs profoundly impacts their antiviral defense responses 117,118 . Rhinovirus, which causes the common cold, is known to replicate more robustly at nasal cavity temperatures of 33–35°C than at core body temperature of 37°C.…”

“…By comparison, human bronchial epithelial cells have relatively attenuated IFN responses during rhinovirus infection. However, other double-stranded RNA-dependent defense responses, including apoptosis and RNAseL activity, can control rhinovirus replication in human epithelial cells, and these responses are also diminished at nasal cavity temperature compared with body temperature 118 . These findings suggest that cooler temperatures in the nasal cavity — which is further cooled when the inhaled air temperature is low — create a niche in which rhinovirus, and perhaps other respiratory viruses, can evade natural antiviral defense mechanisms.…”

Short chain fatty acid butyrate promotes virus infection by repressing interferon stimulated genes

“…Despite the critical role of type I IFNs in antiviral defense, the levels and activities of these IFNs are held in check by dozens of cellular proteins in order to limit their tissue damaging effects (34)(35)(36)(37)(38)(39). In addition to cell-intrinsic regulatory components, recent evidence points to environmental and non-hereditary factors such as ambient temperature and humidity (40)(41)(42), as well as diet and microbiome composition (20,(43)(44)(45)(46)(47), in shaping antiviral immunity. Given the importance of fine-tuning the IFN response, it is likely that many regulatory mechanisms for the IFN induction and signaling pathways remain to be discovered.…”

Contemporary Enterovirus D68 strains show enhanced replication and translation at 37°C

“…When respiratory viruses replicate poorly at 37°C, their infections are often restricted to the upper airways, limiting the potential for damage to the lower respiratory tract and ultimately mitigating disease severity. It is widely accepted that the reason most HRVs cause only mild upper respiratory illness is their preferential replication at cooler physiological temperatures [52][53][54].Temperature sensitivity and restriction to the upper airways has been harnessed for vaccine development and is the basis behind the cold-adapted live attenuated influenza vaccine [55,56]. Historically, in vitro studies indicated EV-D68 replicates optimally at 33°C and is attenuated at higher physiological temperatures [1,4,5].…”