Differential upregulation of AU-rich element-containing mRNAs in COVID-19

Abstract

Background: AU-rich elements (AREs) are located in the 3′UTRs of 22% of human mRNAs, including most transiently expressed inflammatory mediators. By default, AREs mark mRNAs for decay and translational inhibition, but this activity can be temporarily inhibited in case of infection to allow the onset of inflammation. Morbidity and mortality in COVID-19 patients have been associated with dysregulated inflammation, a process that may include aberrant ARE activity. Results: RNA-seq data from available transcriptomic studies were analyzed to investigate a possible differential expression of mRNAs that contain AREs in the context of SARS-CoV-2 infections. ARE-mRNAs turned out to be significantly overrepresented among the upregulated mRNAs after SARS-CoV-2 infection (up to 42%). In contrast, ARE-mRNAs were underrepresented (16%) in the downregulated group. Consequently, at a global scale, ARE-mRNAs are significantly more upregulated after SARS-CoV-2 infection compared to non-ARE mRNAs. This observation was apparent in lung cell line models such as A549 and Calu-3 and with infections with other respiratory viruses and cell lines. Most importantly, at the clinical level, the elevated ARE-mRNA response appeared strongest in blood cells of COVID-19 patients with mild disease. It diminished with disease severity and was least apparent in patients in need of intubation and respiratory-related death. Gene function and clustering analysis suggest that the ARE-response is rather global and the upregulated ARE-mRNAs in patients with mild disease do not particularly cluster in specific functional groups. Conclusions: Compared to the rest of the transcriptome, ARE-containing mRNAs are preferentially upregulated in response to viral infections at a global level. In the context of COVID-19, they are most upregulated in mild disease. Due to their large number, their levels measured by RNA-seq may provide a reliable indication of COVID-19 severity.