Elevated temperature inhibits SARS-CoV2 replication in respiratory epithelium independently of the induction of IFN-mediated innate immune defences

The pandemic spread of SARS-CoV-2, the etiological agent of COVID-19, represents a significant and ongoing international health crisis with over 50 million infections and 1.2 million reported deaths worldwide to date (WHO; November 2020). A key symptom of SARS-CoV-2 infection is the onset of fever, with a hyperthermic temperature range of 38 to 41?C. Fever is an evolutionary conserved host response to microbial infection and inflammation that can influence the outcome of viral pathogenicity and regulation of host innate and adaptive immune responses. However, it remains to be determined what effect elevated temperature has on SARS-CoV-2 tropism and replication within respiratory epithelial tissue. Utilizing a 3D organoid model system that closely mimics the natural tissue physiology and cellular tropism of SARS-CoV-2 infection observed in the respiratory airway, we identify tissue temperature to play an important role in the regulation of SARS-CoV-2 infection within respiratory epithelium. We show temperature elevation to induce wide-spread transcriptome changes that impact upon the regulation of multiple pathways without disruption to tissue integrity, cellular transcription, or the induction of interferon (IFN)-mediated antiviral immune defences. Respiratory tissue incubated at temperatures >37?C remained permissive to SARS-CoV-2 infection but severely restricted the initiation of viral transcription, leading to significantly reduced levels of intra-epithelial viral RNA accumulation and apical shedding of infectious virus. Our data identifies an important role for tissue temperature in the epithelial restriction of SARS-CoV-2 infection that occurs independently of canonical IFN-mediated antiviral immune defences and the induction of interferon stimulated gene (ISG) expression.