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

Abstract

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.

Nanothermometry for cellular temperature monitoring and disease diagnostics

“…111 Since the elderly have lower body temperature than children and young people, the expression of antiviral genes in the elderly is reduced, and the elderly are more threatened by viral infection. 111 In patients with serious sepsis, hyperthermia and hypothermia have different effects on mortality and severity of physiological function decline. 112 Among patients, body temperature below 36.5 ˚C was dramatically related to an elevated risk of death, more than twice as high as in patients with nonhypothermia.…”

“…Without timely cooling treatment, it can induce early multi‐organ damage, rapidly progress to organ failure, and eventually lead to death. For viral infections, an increase in physiological temperature of only 1.5 ˚C from 36.5 ˚C to 38 ˚C strongly increases the antiviral immune response 111 . Since the elderly have lower body temperature than children and young people, the expression of antiviral genes in the elderly is reduced, and the elderly are more threatened by viral infection 111 .…”

ASO targeting temperature-controlledRBM3poison exon splicing prevents neurodegeneration in vivo

“…However, despite evolutionary conservation (3) and extreme temperature sensitivity of this phenomenon (4,5), the mechanistic basis for cold-induced RBM3 expression has remained enigmatic.…”

“…The expression of glycine-rich RNA binding proteins upon cooling, such as CIRBP (Cold-induced RNA binding protein) and RBM3 (RNA binding motif-3), was originally described in the 1990s (Danno et al , 1997; Nishiyama et al , 1997). However, despite evolutionary conservation (Ciuzan et al , 2015) and extreme temperature sensitivity of this phenomenon (Jackson et al , 2015; Los et al , 2022), the mechanistic basis for cold-induced RBM3 expression has remained enigmatic. Our recent identification of temperature-regulated alternative splicing coupled to nonsense-mediated decay (NMD) provides a global mechanism for the control of temperature-dependent gene expression (Neumann et al , 2020).…”

ASO targeting RBM3 temperature‐controlled poison exon splicing prevents neurodegeneration in vivo

“…The expression of glycine‐rich RNA‐binding proteins upon cooling, such as CIRBP (Cold‐induced RNA‐binding protein) and RBM3 (RNA‐binding motif‐3), was originally described in the 1990s (Danno et al , 1997 ; Nishiyama et al , 1997 ). However, despite evolutionary conservation (Ciuzan et al , 2015 ) and extreme temperature sensitivity of this phenomenon (Jackson et al , 2015 ; Los et al , 2022 ), the mechanistic basis for cold‐induced RBM3 expression has remained enigmatic. Our recent identification of temperature‐regulated alternative splicing coupled to nonsense‐mediated decay (NMD) provides a global mechanism for the control of temperature‐dependent gene expression (Neumann et al , 2020 ).…”