期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：36
DOI：10.1073/pnas.2120680119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
SARS-CoV-2–infected patients often display characteristic changes in the production of immune mediators that trigger life-threatening courses of COVID-19. The underlying molecular mechanisms are not yet fully understood. Here, we used single-cell RNA sequencing to investigate the involvement of the emerging class of long regulatory RNA in COVID-19. Our data reveal that a previously unknown regulatory RNA in the nucleus of immune cells is altered after SARS-CoV-2 infection. The degradation of this RNA removes a natural brake on the production of critical immune mediators that can promote the development of severe COVID-19. We believe that therapeutic intervention in this nuclear RNA circuit could counteract the overproduction of disease-causing immune mediators and protect against severe 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.
