Elevated temperature inhibits SARS-CoV-2 replication in respiratory epithelium independently of IFN-mediated innate immune defenses

Abstract

The pandemic spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of Coronavirus Disease 2019 (COVID-19), represents an ongoing international health crisis. 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 evolutionarily conserved host response to microbial infection 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 replication. Utilizing a three-dimensional (3D) air–liquid interface (ALI) model that closely mimics the natural tissue physiology of SARS-CoV-2 infection in the respiratory airway, we identify tissue temperature to play an important role in the regulation of SARS-CoV-2 infection. Respiratory tissue incubated at 40°C remained permissive to SARS-CoV-2 entry but refractory to viral transcription, leading to significantly reduced levels of viral RNA replication and apical shedding of infectious virus. We identify tissue temperature to play an important role in the differential regulation of epithelial host responses to SARS-CoV-2 infection that impact upon multiple pathways, including intracellular immune regulation, without disruption to general transcription or epithelium integrity. We present the first evidence that febrile temperatures associated with COVID-19 inhibit SARS-CoV-2 replication in respiratory epithelia. Our data identify an important role for tissue temperature in the epithelial restriction of SARS-CoV-2 independently of canonical interferon (IFN)-mediated antiviral immune defenses.

Time-resolved characterization of the innate immune response in the respiratory epithelium of human, porcine, and bovine during influenza virus infection

“…Nonetheless, as fever is an evolutionary conserved response to viral and bacterial infections (64,65), it would be of interest to assess the viral replication efficiency and host response dynamics at hyperthermic temperatures (39 -41°C) during ICV and IDV infection in different host species. Especially as, in contrast to lower ambient temperatures, viral replication in human airway epithelial cells has previously been described to be restricted at high ambient temperatures independently of the host IFN-mediated antiviral immune response (66). Therefore, given the economic importance of pigs and cows and their role as a host reservoir of potential emerging diseases, detailed thermal mapping at different anatomical regions in the respiratory tract, as well as determining the influence of hyperthermic temperatures on ICV and IDV replication efficiency and cross species transmission among these host species remain warranted.…”

The life and death of RNA across temperatures

“…Fever-like temperatures have been shown to reduce transcription of SARS-CoV-2 and hence their replication in respiratory epithelium. This phenomenon was specifically due to inhibition of transcription since the virus entry into the cells was intact [87] . The mechanism of the temperature dependence remains to be determined.…”

Decoding the Role of Temperature in RNA Virus Infections

“…2 ). An additional increase in temperature to 39°C and 40°C limited the rate of viral RNA synthesis and reduced the viral titer even further ( 53 ) ( Fig. 2 ).…”

“…The temperature at which RNA synthesis and virion assembly take place impacts the folding of RNA secondary structures in the genome and protein-RNA and protein-protein interactions, as well as the conformation and activity of viral enzymes ( 48 – 52 ). The temperature at the time of the infection also affects the innate immune response triggered by the infection and production of viral RNA molecules ( 53 – 55 ) and thereby viral growth and the transmission efficiency. Knowledge of the impact of temperature on viral RNA synthesis, the immune response, and the stability of RNA viruses in different environments is important for our understanding of their transmissibility and the design of antiviral strategies, as well as for estimating the likelihood that humans may contract spillover RNA viruses in the future.…”