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

Abstract

The pandemic spread of SARS-CoV-2, the etiological agent of COVID-19, represents a significant and 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 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. Utilizing a 3D air-liquid interface (ALI) model that closely mimics the natural tissue physiology and cellular tropism 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. We show that temperature elevation induces wide-spread transcriptome changes that impact upon the regulation of multiple pathways, including epigenetic regulation and lncRNA expression, without disruption of general 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 intraepithelial viral RNA accumulation and apical shedding of infectious virus. To our knowledge, we present the first evidence that febrile temperatures associated with COVID-19 inhibit SARS-CoV-2 replication. Our data identify an important role for temperature elevation in the epithelial restriction of SARS-CoV-2 that occurs independently of the induction of canonical IFN-mediated antiviral immune defences and interferon-stimulated gene (ISG) expression.

Impact of temperature on the affinity of SARS-CoV-2 Spike glycoprotein for host ACE2

“…This was linked to Spike stability which was enhanced by the introduction of the D614G mutation ( 18 , 19 , 20 ) but also enhanced its use of cell-surface and endosomal proteases ( 17 , 21 ). Additionally, recent studies have noticed an increase replication of SARS-CoV-2 in primary human airway epithelial cells at 33°C compared to 37°C ( 22 ), while higher temperatures (39°C-40°C) decreased overall viral replication ( 23 ). Since it was previously documented that temperature modulates the affinity of another viral envelope glycoprotein (HIV-1 Env) for its receptor ( 24 ), herein, we evaluate to what extent temperature affects the interaction of SARS-CoV-2 Spike with ACE2, and concomitantly, its effect on viral attachment.…”

Impact of temperature on the affinity of SARS-CoV-2 Spike for ACE2

“…This was linked to Spike stability which was enhanced by the introduction of the D614G mutation (18–20) but also enhanced its use of cell-surface and endosomal proteases (17, 21). Additionally, recent studies have noticed an increase replication of SARS-CoV-2 in primary human airway epithelial cells at 33°C compared to 37°C (22), while higher temperatures (39°C-40°C) decreased overall viral replication (23). Since it was previously documented that affinity of viral envelope glycoproteins for their receptor is modulated by temperature (24), herein, we evaluate to what extent temperature affects the interaction of SARS-CoV-2 Spike with ACE2, and concomitantly, its effect on viral attachment.…”

Deciphering epigenetic(s) role in modulating susceptibility to and severity of COVID-19 infection and/or outcome: a systematic rapid review

“…COVID-19-associated febrile temperatures were shown to induce widespread changes in the transcriptome that would affect the regulation of multiple epigenetic pathway dysregulation as one of the hallmarks of CoV-2 infection, one of which is lncRNA expression, that can lead to SARS-CoV-2 replication inhibition (Herder et al 2020).…”