Body temperature variation controls pre-mRNA processing and transcription of anti-viral genes

Anti-viral innate immunity represents the first line of defense against invading viruses and is key to control viral infections, including the pandemic SARS-CoV-2. Body temperature is an omnipresent variable but was so far 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°C and 38°C, strongly increases anti-viral immunity. 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 anti-viral genes. This cascade is activated in a remarkably narrow temperature range below febrile temperature, which reflects individual, circadian and age-dependent body temperature variation. Accordingly, decreased body temperature with ageing correlates with reduced expression of anti-viral genes in older individuals. Using cell culture and in vivo models, we show that higher body temperature indeed reduces SARS-CoV-2 replication, which likely impacts on the different vulnerability of children versus seniors towards severe SARS-CoV-2 infection. Altogether, our data reveal a molecular mechanism, from temperature sensing and pre-mRNA processing to an in vivo phenotype connecting body temperature variation with SARS-CoV-2 replication, thus providing a new paradigm for the regulation of anti-viral innate immunity. Raw264.7. Cells were incubated for 12h at 34°C, 37°C or 38°C