The regulation and function of viperin during rhinovirus infection
Date
2022-12-19
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Abstract
The airway epithelium is the primary site of rhinovirus replication and plays a pivotal role in orchestrating innate immune responses to respiratory viruses, including rhinovirus. Interfacing with inhaled material in the airway lumen, the airway epithelium experiences continuous onslaught from respiratory pathogens. To combat viral infection, cells of the airway epithelium express a range of pattern recognition receptors capable of recognizing diverse viral ligands. Detection of an infectious virus by one of these receptors rapidly upregulates an array of effector molecules, including pro-inflammatory cytokines, interferons and interferon stimulated genes. Viperin is one of the most highly upregulated interferon stimulated genes in rhinovirus infected airway epithelial cells. Viperin expression during viral infection has long been associated with direct antiviral effects across diverse viral infection and cell models, including in rhinovirus infected airway epithelial cells. Despite the long-standing knowledge that viperin expression helps to impedes rhinovirus replication in the airway epithelium, little is known about how it is upregulated in response to rhinoviruses or how viperin proceeds to impact airway epithelial cell biology during infection. In addition to confirming previously published findings demonstrating that viperin is induced in rhinovirus infected primary human airway epithelial cells and is dependent on viral replication, we also demonstrated induction of viperin in airway epithelial cells by interferons. We also highlight the importance of the type III interferon IL-29 as a potent inducer of viperin in the airway epithelium. Finally based on our findings we propose a novel feedback loop, according to this model detection of rhinoviruses by the cytosolic dsRNA receptor melanoma differentiation-associated protein 5 (MDA5), or IL-29 signalling, promotes IRF-1 mediated viperin transcription. Viperin then establishes a protein-protein interaction with MDA5 which results in enhanced MDA5 stability in RV infected cells. This leads to enhanced signalling through MDA5, as measured by increased CXCL10 gene expression and protein secretion. As we have also demonstrated that MDA5 signalling is involved in promoting viperin expression in response to RV we hypothesize that stabilization of MDA5 by viperin may also serves to amplify viperin production during infection.
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Keywords
viperin, airway epithelium, rhinovirus, innate immunity
Citation
Love, M. (2022). The regulation and function of viperin during rhinovirus infection (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.