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SARS-CoV-2-associated ssRNAs activate human neutrophils in a TLR8-dependent fashion

ABSTRACT: SARS-CoV-2-associated ssRNAs activate human neutrophils in a TLR8-dependent fashion

PROVIDER: PRJNA884619 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21721700.fastq.gz	Fastqsanger.gz
	SRR21721701.fastq.gz	Fastqsanger.gz
	SRR21721702.fastq.gz	Fastqsanger.gz
	SRR21721703.fastq.gz	Fastqsanger.gz
	SRR21721704.fastq.gz	Fastqsanger.gz

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SARS-CoV-2-associated ssRNAs activate human neutrophils in a TLR8-dependent fashion

Project description:COVID-19 disease is characterized by a dysregulation of the innate arm of the immune system. However, the mechanisms whereby innate immune cells, including neutrophils, become activated in patients are not completely understood. Recently, we showed that a GU-rich RNA sequence from SARS-CoV-2 genome (i.e., SCV2-RNA2) activates dendritic cells. To clarify whether human neutrophils may also represent targets of SCV2-RNA2, neutrophils were treated with either SCV2-RNA2 or, as control, R848 (a TLR7/8 ligand), and then analysed for several functional assays and also subjected to RNA-seq experiments. Results highlight a remarkable response of neutrophils to SCV2-RNA2 in terms of TNFa, IL1ra, CXCL8 production, apoptosis delay, modulation of CD11b and CD62L expression and release of neutrophil extracellular traps. By RNA-seq experiments, we observed that SCV2-RNA2 promotes a transcriptional reprogramming of neutrophils, characterized by the induction of thousands of proinflammatory genes, similarly to that promoted by R848. Furthermore, by using CU-CPT9a, a TLR8-specific inhibitor, we found that SCV2-RNA2 stimulates neutrophils exclusively via TLR8-dependent pathways. In sum, our study proves that single-strand RNAs from the SARS-CoV-2 genome potently activate human neutrophils via TLR8, thus uncovering a potential mechanism whereby neutrophils may contribute to the pathogenesis of severe COVID-19 disease.

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Project description:Mechanistic studies have revealed that TLR8 senses single-stranded RNA (ssRNA) fragments, processed via synergistic cleavage by ribonucleases (RNase) T2 and RNase A family members. Processing by these RNases releases uridines and purine-terminated residues resulting in TLR8 activation. Monocytes show high expression of RNase 6, yet this RNase has not been analyzed for its physiological contribution to recognition of bacterial RNA by TLR8. Herein, we characterized molecular RNase 6 cleavage mechanisms. BLaER1 RNASE6-/- cells showed a dampened TLR8-dependent response upon stimulation with isolated bacterial RNA (bRNA) but also upon infection with live whole bacteria. Pretreatment of bacterial RNA with recombinant RNase 6 generated fragments that induced stimulation in RNASE6 knockout cells. 2’O-RNA methyl modification, when introduced at the first uridine in the UA dinucleotide, impaired upstream processing by RNase 6 and dampened TLR8 stimulation. In summary, this data shows that RNase 6 plays a critical role in the processing of bacterial RNA by generating uridine-terminated breakdown products that ultimately activate TLR8.

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Project description:The severity of COVID-19 is linked to excessive inflammation. Neutrophils represent a critical arm of the innate immune response and are major mediators of inflammation, but their role in COVID-19 pathophysiology remains poorly understood. We conducted transcriptomic profiling of neutrophils obtained from SARS-CoV-2 infected mice, in comparison to non-infected healthy controls. In addition, we investigated the inflammasome formation potential in neutrophils from mice upon SARS-CoV-2 infection. Transcriptomic analysis of polymorphonuclear cells (PMNs), consisting mainly of mature neutrophils, revealed a striking type I interferon (IFN-I) gene signature in infected mice. Furthermore, IFN-I emerged as a priming stimulus for neutrophil inflammasomes, which was confirmed in a COVID-19 mouse model. These findings underscore the crucial role of neutrophil inflammasomes in driving inflammation during severe COVID-19. Altogether, these findings open promising avenues for targeted therapeutic interventions to mitigate the pathological processes associated with the disease.

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