epiRNAcovid

We will here explore the mechanisms allowing for SARS-COV2-induced pervasive transcription and determine the role of the resulting non-coding RNAs (ncRNAs) in the inflammatory phenotype of COVID19 patients. We find that SARS-CoV2, alike the influenza A virus, interferes with transcriptional termination and thereby induces production of transcripts that exceed gene boundaries and end up in the intergenic regions. Due to the abundance of transposable elements in these regions normally inaccessible to transcription, these RNA polymerase II passages provide a source of repeat-rich RNAs that may feed the pool of double-stranded RNAs (dsRNAs). The accumulation of these dsRNAs in the cytoplasm of infected cells participates in the activations of anti-viral receptors of the innate immunity. The genome-encoded dsRNAs may serve the virus by decoying cellular defense mechanisms, or the host by amplifying the immune response. In either scenario, they represent a source of inflammatory mediators that may persist even after the clearance of the virus, potentially contributing to the development of long COVID symptoms. To reach better understanding of the phenomenon, the present consortium associates expertises in chromatin and RNA maturation (E. Batsché, Sorbonne Université) and in SARS CoV2 biotechnology (B. Delmas, INRAE, Jouy-en-Josas) with an emergency clinician specialized in inflammation/sepsis (F. Uhel, INEM, Paris). Specifically, the consortium wishes to (1) characterize the chain of events linking transcription downstream of genes to the production of double-stranded RNAs liable to activate host pattern recognition receptors (PRRs), (2) identify the mechanisms allowing SARS-CoV2 to induce accumulation of pervasive transcripts, with a focus both on their increased production and on their reduced turnover, (3) connect the accumulation of these transcripts to the clinical outcome for SARS-CoV2, and then explore the value of identified signature RNAs in COVID-19 prognostic and diagnostic. This latter work package will rely both on COVID-19 patient biopsies and on an animal model (golden syrian hamster). Altogether, we expect to unravel a novel pathway triggering an antiviral response via termination defects and subsequent transcription of repeat-rich 3’ regions of genes. As this transcription may perdure after the clearance of the SARS-CoV-2 virus, it will provide new insight on long-lasting COVID-19 symptoms. In addition, our approaches will yield signature RNAs amenable to diagnostic tests, and identify possibly druggable viral targets for more effective management of the disease. These knowledge and tools are expected to have implications beyond the recent pandemic, and will be valuable in addressing future public health challenges.