Moderator of 1 Session
Presenter of 2 Presentations
LC3B2 and ATG4A, Autophagy and Meningitis
IDENTIFICATION OF HOST GENETIC VARIANTS IN THE CYTOSOLIC DNA SENSOR POL III IN PATIENTS WITH CRITICAL COVID-19
Abstract
Background and Aims
The underlying pathogenesis explaining why some individuals develop life-threatening COVID-19 disease remains incompletely understood. In this study we aim to identify gene variants predisposing specifically to vary rare cases of critical COVID-19 in young individuals without co-morbidities.
Methods
By whole exome sequencing we have identified potential disease-causing host gene variants in younger patients with critical COVID-19.
Results
We have revealed an accumulation of mutations in genes encoding the innate cytosolic DNA sensor RNA polymerase III (POL III) in younger patients with critical COVID-19. In peripheral blood mononuclear cells (PBMCs) isolated from patients with identified POL III gene variants, we have shown reduced type I interferon (IFN) responses to SARS-CoV-2 and the POL III agonist poly(dAdT). Likewise, inhibition of POL III in the pulmonary cell line A549 resulted in reduced IFN response to SARS-CoV-2. Currently, we are further scrutinizing the impact of POL III gene variants on the development of critical COVID-19 by investigating how the DNA sensor POL III is sensing infections with RNA-viruses, like SARS-CoV-2. We hypothesize that mitochondrial DNA released into the cytosol due to SARS-CoV-2-induced cellular stress during infection is sensed by POL III and mediating induction of IFN expression.
Conclusions
By regulating the IFN response to SARS-CoV-2 POL III seems to be important for prevention of development of critical COVID-19. Studies to examine the molecular mechanism, whereby host DNA may serve an antiviral role during SARS-CoV-2 infection are ongoing. Hence, this study provides new knowledge on the role of cytosolic DNA sensing and POL III in severe viral infections.