Ontology highlight
ABSTRACT:
PROVIDER: PRJNA688898 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13361166.fastq.gz | Fastqsanger.gz | |||
| SRR13361167.fastq.gz | Fastqsanger.gz | |||
| SRR13361168.fastq.gz | Fastqsanger.gz | |||
| SRR13361169.fastq.gz | Fastqsanger.gz | |||
| SRR13361170.fastq.gz | Fastqsanger.gz |
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Project description:In 2014, enterovirus D68 (EV-D68), previously associated primarily with mild respiratory illness, caused a large outbreak of severe respiratory illness and, in rare instances, paralysis. We compared viral binding and replication of eight recent EV-D68 clinical isolates and the prototype Fermon strain from 1962 in cultured HeLa cells and differentiated human primary bronchial epithelial cells (BEC) to understand the possible reasons for the change in virus pathogenicity. We found no significant differences in binding or replication in HeLa cell cultures between the recent clinical isolates. However, in HeLa cells, Fermon had significantly greater (1.5-2 log) binding and virus progeny yields but a similar level of replication (~2-log increase in viral RNA from 2h to 24h post infection) compared to recent isolates. In differentiated BECs, Fermon and the recent EV-D68 isolates had similar levels of binding; however, the recent isolates produced 1-2-log higher virus progeny yields than Fermon due to increased replication. We then utilized RNA-seq to define the transcriptional responses in BECs infected with four recent EV-D68 isolates, representing major phylogenetic clades, and Fermon strain. All the tested clinical isolates induced similar responses in BECs; however, numerous upregulated genes in antiviral and pro-inflammatory response pathways were identified when comparing the response to clinical isolates versus Fermon. These results indicate that the recent emergence in severe EV-D68 cases could be explained by increased replication efficiency and enhanced inflammatory response induced by newly emerged clinical isolates.
2023-07-06 | GSE233630 | GEO
Project description:Enteroviruses (EVs) are one of the most prevalent viruses worldwide. They are characterised by a high genetic and phenotypic diversity, being able to cause a plethora of symptoms. EV-D68, a respiratory EV, and EV-D94, an enteric EV, represent an interesting paradigm of EV tropism heterogeneity. These are closely related viruses, belonging to the same species, but with distinct phenotypic features. Here, we used these two viruses as well as relevant tissue culture models mimicking the respiratory and intestinal epithelia, to highlight key distinctive features of enteric and respiratory EVs. We emphasize the critical role of temperature in restricting the tissue tropism of EV-D68 and the limited replication of EV-D94 in small airway tissues. In parallel, using transcriptomic analysis, we uncover fundamental differences between intestinal and respiratory tissues, in their steady-state as well as in response to infection. Intestinal tissues are more immunotolerant than respiratory tissues both in absence and presence of infection and they present higher turnover. Finally, we highlight the different strategies applied by EV-D94 and EV-D68 towards the host antiviral response in intestinal and respiratory tissues. In summary, our study provides an insightful characterization of the differential pathogenesis of EV-D68 and EV-D94 and the interplay with their main target tissues.
2022-06-23 | GSE184488 | GEO
Project description:Respiratory viruses pose an ongoing threat to human health, with excessive cytokine secretion playing a critical role in severe illness and mortality. However, the complex relationship between cytokine secretion and viral infection remains poorly understood. Here, we have unraveled the role of cxcl8 as an early response gene to respiratory EV-D68 infection. The upregulation of CXCL8 by viral infection is found to be crucial for EV-D68 replication. Importantly, silencing CXCL8 or its receptors, CXCR1/2, significantly impedes EV-D68 replication. Upon recognition of CXCL8 by CXCR1/2, the MAPK pathway is activated, facilitating the translocation of the essential host cofactor hnRNP K from the nucleus to the cytoplasm. This translocation enhances the recognition of viral RNA by hnRNP K in the cytoplasm, promoting the functionality of the 5’UTR region in the viral genome. Interestingly, the VP4 structural protein of EV-D68 contains a mimic motif of human immunoreceptor tyrosine-based activation motif (ITAM) that interacts with syk and triggers the PI3K/AKT signaling pathway, resulting in elevated CXCL8 gene expression for viral replication. Moreover, our investigations reveal the conservation and significance of the CXCL8 signaling pathway across various prominent human respiratory viruses, including SARS-CoV-2, influenza, and rhinovirus. In summary, our findings unveil a paradigmatic mechanism through which respiratory viruses exploit cytokine-mediated intercellular communication to transmit signals that optimize viral replication. This deepens our understanding of the shared evolutionary strategies employed by respiratory viruses and opens up new avenues for the development of broad-spectrum antiviral drugs targeting respiratory pathogens.
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Project description:With the near eradication of poliovirus due to global vaccination campaigns, attention has shifted to other enteroviruses that can cause polio-like paralysis syndrome (now termed acute flaccid myelitis (AFM)). In particular, enterovirus D68 (EV-D68) is believed to be the main driver of epidemic outbreaks of AFM in recent years, yet not much is known about EV-D68 host interactions. EV-D68 is a respiratory virus but, in rare cases, can spread to the central nervous system to cause severe neuropathogenesis. We use genome-scale CRISPR screens to identify genes important for EV-D68 infection. A549 and U87-MG cells were stably transduced with lentiCas9-Blast (Addgene, #52962) and subsequently selected using Blasticidin. Then, 300 million cells that constitutively express Cas9 were transduced with lentiGuide-Puro from the Brunello library (MOI 0.3). Cells were then selected with puromycin, expanded to 3 billion cells, and then pooled together and cryofrozen in aliquots. One hundred million cells were thawed constituting over 1000× genome coverage worth of mutagenized library,expanded, and seeded for the screens. Each screen had over 500x genome coverage. The cells were infected with EV-D68 IL (BEI USA/2014/18952) (MOI 0.1). Virus-resistant colonies were harvested. The uninfected reference used was the unselected starting population. The unselected and selected cells were both processed with QIAamp DNA columns to purify the gDNA. A first round of PCR was used to amplify the guide RNA sequences encoded in the gDNA, followed by a second round of PCR to add the barcodes/adapters for amplicon sequencing. 2% agarose gels and a QIAquick gel extraction kit were used to purify the amplicons. The amplicons were then subjected to next-generation sequencing on a HiSeq instrument lane (Illumina) via Novogene.
2025-02-25 | E-MTAB-14765 | biostudies-arrayexpress
Project description:The mechanisms by which enteroviruses, particularly enterovirus D-68 (EV-D68) and enterovirus A-71 (EV-A71), contribute to acute flaccid myelitis (AFM), a severe neurological condition characterized by sudden muscle weakness and paralysis, remain poorly understood. To investigate the cellular tropism and infection dynamics of these enteroviruses, we utilized human spinal cord organoids (hSCOs) derived from induced pluripotent stem cells (iPSCs). We performed single-cell RNA sequencing (scRNA-seq) to profile the cellular composition of hSCOs and identify infected cell types post-infection. We found that hSCOs exhibit a diverse cellular landscape, including neurons, astrocytes, oligodendrocyte progenitor cells (OPCs), and multipotent glial progenitor cells (mGPCs), with astrocytes predominant in earlier developmental stages and neurons more abundant in later stages. Upon infection with two EV-D68 strains (US/IL/14-18952 and US/CO/18-23089) and one EVA71 strain (Tainan/4643/1998), we observed distinct viral tropism. EV-D68-18952 showed a significant increase in infected neurons, while EV-D68-23089 exhibited higher infection rates in cycling astrocytes and OPCs. In contrast, EVA71 demonstrated a broader tropism, with a statistically significant increase in infected mGPCs, suggesting enhanced infection efficiency across multiple cell types. These findings provide novel insights into the cell-type specificity of EV-D68 and EVA71 in the spinal cord, offering a deeper understanding of potential mechanisms underlying AFM pathogenesis. Understanding the dynamics of infection at single-cell resolution will inform future therapeutic strategies aimed at mitigating the neurological impact of enteroviral infections.
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Project description:Viral respiratory infections significantly affect young children, particularly extremely premature infants, resulting in high hospitalization rates and increased health-care burdens. Despite posing substantial health risks, airway immune responses in early life remain largely unexplored. Nasal epithelial cells, the primary defense against respiratory infections, are vital for understanding nasal immune responses and serve as a promising target for uncovering underlying molecular and cellular mechanisms. Using a trans-well pseudostratified nasal epithelial cell system, we examined age-dependent developmental differences and antiviral responses to influenza A and respiratory syncytial virus through systems biology approaches. Our studies revealed differences in innate-receptor repertoires, distinct developmental pathways, and differentially connected antiviral network circuits between neonatal and adult nasal epithelial cells. Consensus network analysis identified unique and shared cellular networks for influenza A and respiratory syncytial virus, emphasizing highly relevant virus-specific pathways. This research highlights the importance of nasal epithelial cells in innate antiviral immune responses and offers novel insights that should enable a deeper understanding of age-related differences in nasal epithelial cell immunity following respiratory virus infections.
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Project description:Coronavirus (CoV) Nsp15 is a viral endoribonuclease (EndoU) with a preference for uridine residues. CoV Nsp15 is an innate immune antagonist which prevents dsRNA sensor recognition and stress granule formation by targeting viral and host RNAs. SARS-CoV-2 restricts and delays the host antiviral innate immune responses through multiple viral proteins, but the role of SARS-CoV-2 Nsp15 in innate immune evasion is not completely understood. Here, we generate an EndoU activity knockout rSARS-CoV-2Nsp15-H234A to elucidate the biological functions of Nsp15. Relative to wild-type rSARS-CoV-2, replication of rSARS-CoV-2Nsp15-H234A was significantly decreased in IFN-responsive A549-ACE2 cells but not in its STAT1 knockout counterpart. Transcriptomic analysis revealed upregulation of innate immune response genes in cells infected with rSARS-CoV-2Nsp15-H234A relative to wild-type virus, including cGAS-STING, cytosolic DNA sensors activated by both DNA and RNA viruses. Treatment with STING inhibitors H-151 and SN-011 rescued the attenuated phenotype of rSARS-CoV-2Nsp15-H234A. SARS-CoV-2 Nsp15 inhibited cGAS-STING-mediated IFN-β promoter and NF-κB reporter activity, as well as facilitated the replication of EV-D68 and NDV by diminishing the expression of cGAS and STING and downstream innate immune responses. Notably, the decline in cGAS and STING was also apparent during SARS-CoV-2 infection. The EndoU activity was essential for SARS-CoV-2 Nsp15-mediated cGAS and STING downregulation, but not all HCoV Nsp15 share the consistent substrate selectivity. In the hamster model, rSARS-CoV-2Nsp15-H234A replicated to lower titers in the nasal turbinates and lungs and induced higher innate immune responses. Collectively, our findings exhibit that SARS-CoV-2 Nsp15 serves as a host innate immune antagonist by targeting host cGAS and STING.
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