Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19

The systemic immune response to viral infection is shaped by master transcription factors, such as NF-κB, STAT1, or PU.1. Although long noncoding RNAs (lncRNAs) have been suggested as important regulators of transcription factor activity, their contributions to the systemic immunopathologies observed during SARS-CoV-2 infection have remained unknown. Here, we employed a targeted single-cell RNA sequencing approach to reveal lncRNAs differentially expressed in blood leukocytes during severe COVID-19. Our results uncover the lncRNA PIRAT (PU.1-induced regulator of alarmin transcription) as a major PU.1 feedback-regulator in monocytes, governing the production of the alarmins S100A8/A9, key drivers of COVID-19 pathogenesis. Knockout and transgene expression, combined with chromatin-occupancy profiling, characterized PIRAT as a nuclear decoy RNA, keeping PU.1 from binding to alarmin promoters and promoting its binding to pseudogenes in naïve monocytes. NF-κB-dependent PIRAT down-regulation during COVID-19 consequently releases a transcriptional brake, fueling alarmin production. Alarmin expression is additionally enhanced by the up-regulation of the lncRNA LUCAT1, which promotes NF-κB-dependent gene expression at the expense of targets of the JAK-STAT pathway. Our results suggest a major role of nuclear noncoding RNA networks in systemic antiviral responses to SARS-CoV-2 in humans.

• Aznaourova, M.
• Schmerer, N.
• Janga, H.
• Zhang, Z.
• Pauck, K.
• Bushe, J.
• Volkers, S. M.
• Wendisch, D.
• Georg, P.
• Ntini, E.
• Aillaud, M.
• Gündisch, M.
• Mack, E.
• Skevaki, C.
• Keller, C.
• Bauer, C.
• Bertrams, W.
• Marsico, A.
• Nist, A.
• Stiewe, T.
• Gruber, A. D.
• Ruppert, C.
• Li, Y.
• Garn, H.
• Sander, L. E.
• Schmeck, B.
• Schulte, L. N.