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

Abstract

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.

Transcriptomic study reveals lncRNA-mediated downregulation of innate immune and inflammatory response in the SARS-CoV-2 vaccination breakthrough infections

“…LUCAT1, apart from regulating the IFN genes, also regulates NF-kB dependent genes by modulating the JAK-STAT pathway. Another lncRNA, PIRAT, regulates the expression of alarmins S100A8/A9 in the monocytes, which are essential for the pathogenesis of COVID-19 (66). Apart from the previously discussed regulation of immune and inflammatory response, MALAT1 is also known to regulate the IFNG gene regulation by modulating HIF-1 through has-miR-155-5p (67).…”

Aid or Antagonize: Nuclear Long Noncoding RNAs Regulate Host Responses and Outcomes of Viral Infections

“…The SARS-CoV-2 infection also enhances the expression of another lncRNA, LUCAT1 , which augments alarmin gene transcription. Thus, the SARS-CoV-2 infection upregulates LUCAT1 and downregulates PIRAT , increasing alarmin production and aggravating inflammatory mediators contributing to the severity of COVID-19 [ 168 ]. LncRNA LUARIS (a.k.a.…”

Long non-coding RNA SNHG9 regulates viral replication in rhabdomyosarcoma cells infected with enterovirus D68 via miR-150-5p/c-Fos axis

“…Recent studies have shown that lncRNAs affect gene expression and are critical for pathological processes such as cancer and inflammatory response ( Chew et al, 2018 ; Liu et al, 2021 ; Gysens et al, 2022 ). In addition, more and more data indicate that the altered lncRNA expression is closely related to the pathogenesis of viral infection ( Yin et al, 2013 ; Aznaourova et al, 2022 ; Basavappa et al, 2022 ; Li H. et al, 2022 ; Liu et al, 2022 ): The lncRNA ALPHA targets chikungunya virus to limit infection ( Basavappa et al, 2022 ). Single-cell RNA sequencing reveals the nuclear decoy lncRNA PIRAT as a modulator of systemic monocyte immunity during COVID-19 infection ( Aznaourova et al, 2022 ).…”

“…In addition, more and more data indicate that the altered lncRNA expression is closely related to the pathogenesis of viral infection ( Yin et al, 2013 ; Aznaourova et al, 2022 ; Basavappa et al, 2022 ; Li H. et al, 2022 ; Liu et al, 2022 ): The lncRNA ALPHA targets chikungunya virus to limit infection ( Basavappa et al, 2022 ). Single-cell RNA sequencing reveals the nuclear decoy lncRNA PIRAT as a modulator of systemic monocyte immunity during COVID-19 infection ( Aznaourova et al, 2022 ). However, the function of lncRNAs in EV-D68 infection is uncertain.…”