Body temperature variation controls pre-mRNA processing and transcription of antiviral genes and SARS-CoV-2 replication

Los et al., Nucleic Acids Research, doi:10.1093/nar/gkac513

Jun 2022

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In Vitro and hamster study showing that higher temperature reduces SARS-CoV-2 replication. Authors show a 1.5°C increase in temperature (from 36.5 to 38°C) enhanced the expression of antiviral genes. Elevated temperatures were found to reduce SARS-CoV-2 replication in cell cultures of Calu-3 and Caco-2 cells. An in vivo hamster model indicated that higher body temperature at the time of infection correlated with lower viral loads.

7 preclinical studies support the efficacy of indomethacin for COVID-19:

3 In Silico studies1-3

4 In Vitro studies1,4-6

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Study covers thermotherapy, acetaminophen, ibuprofen, and indomethacin.

1. Metwaly et al., Discovery of potential FDA-approved SARS-CoV-2 Papain-like protease inhibitors: A multi-phase in silico approach, Journal of Chemical Research, doi:10.1177/17475198241298547.sagepub.com, doi.org.

2. Agamah et al., Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases, ScienceOpen, doi:10.58647/DRUGARXIV.PR000010.v1.scienceopen.com, doi.org.

3. Chakraborty et al., In-silico screening and in-vitro assay show the antiviral effect of Indomethacin against SARS-CoV-2, Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2022.105788.sciencedirect.com, doi.org.

4. Tramontozzi et al., Indomethacin inhibits human seasonal coronaviruses at late stages of viral replication in lung cells: Impact on virus-induced COX-2 expression, Journal of Virus Eradication, doi:10.1016/j.jve.2024.100387.sciencedirect.com, doi.org.

5. Wang et al., Combating pan-coronavirus infection by indomethacin through simultaneously inhibiting viral replication and inflammatory response, iScience, doi:10.1016/j.isci.2023.107631.sciencedirect.com, doi.org.

6. Souza et al., Analysis of the effects of indomethacin on SARS-CoV-2 infection and the inflammatory response associated with the purinergic system, Master's Dissertation, repositorio.ufsm.br/handle/1/29252.ufsm.br.

Los et al., 17 Jun 2022, peer-reviewed, 12 authors. Contact: florian.heyd@fu-berlin.de.

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Body temperature variation controls pre-mRNA processing and transcription of antiviral genes and SARS-CoV-2 replication

Bruna Los, Marco Preußner, Kathrin Eschke, Ricardo Martin Vidal, Azza Abdelgawad, Didrik Olofsson, Sandra Keiper, Margarida Paulo-Pedro, Alica Grindel, Stefan Meinke, Jakob Trimpert, Florian Heyd

Nucleic Acids Research, doi:10.1093/nar/gkac513

Antiviral innate immunity represents the first defense against invading viruses and is key to control viral infections, including SARS-CoV-2. Body temperature is an omnipresent variable but was neglected when addressing host defense mechanisms and susceptibility to SARS-CoV-2 infection. Here, we show that increasing temperature in a 1.5 • C window, between 36.5 and 38 • C, strongly increases the expression of genes in two branches of antiviral immunity, nitric oxide production and type I interferon response. We show that alternative splicing coupled to nonsense-mediated decay decreases STAT2 expression in colder conditions and suggest that increased STAT2 expression at elevated temperature induces the expression of diverse antiviral genes and SARS-CoV-2 restriction factors. This cascade is activated in a remarkably narrow temperature range below febrile temperature, which reflects individual, circadian and age-dependent variation. We suggest that decreased body temperature with aging contributes to reduced expression of antiviral genes in older individuals. Using cell culture and in vivo models, we show that higher body temperature correlates with reduced SARS-CoV-2 replication, which may affect the different vulnerability of children versus seniors toward severe SARS-CoV-2 infection. Altogether, our data connect body temperature and pre-mRNA processing to provide new mechanistic insight into the regulation of antiviral innate immunity.

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