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Desmoglein 2 is a crucial receptor for adenovirus infection of epithelial cells

ABSTRACT: We have identified desmoglein 2 (DSG2) as the primary high-affinity receptor used by adenovirus (Ad) serotypes Ad3, Ad7, and Ad14. These serotypes represent important human pathogens causing respiratory tract infections. In epithelial cells, adenovirus binding to DSG2 triggers events reminiscent of epithelial-to-mesenchymal transition, leading to transient opening of intercellular junctions. This improves access to receptors, e.g. CD46 and Her2/neu, that are trapped in intercellular junctions. In addition to complete virions, dodecahedral particles (PtDd) formed by viral penton and fiber in excess during viral replication, can trigger DSG2-mediated opening of intercellular junctions as shown by studies with recombinant Ad3 PtDd. Our findings shed light on adenovirus biology and pathogenesis and have implications for cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE24138 | GEO | 2010/12/08

SECONDARY ACCESSION(S): PRJNA130015

REPOSITORIES: GEO

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Desmoglein 2 is a crucial receptor for adenovirus infection of epithelial cells

Project description:We have identified desmoglein 2 (DSG2) as the primary high-affinity receptor used by adenovirus (Ad) serotypes Ad3, Ad7, and Ad14. These serotypes represent important human pathogens causing respiratory tract infections. In epithelial cells, adenovirus binding to DSG2 triggers events reminiscent of epithelial-to-mesenchymal transition, leading to transient opening of intercellular junctions. This improves access to receptors, e.g. CD46 and Her2/neu, that are trapped in intercellular junctions. In addition to complete virions, dodecahedral particles (PtDd) formed by viral penton and fiber in excess during viral replication, can trigger DSG2-mediated opening of intercellular junctions as shown by studies with recombinant Ad3 PtDd. Our findings shed light on adenovirus biology and pathogenesis and have implications for cancer therapy. 3 arrays, 3 experimental groups, 1 replicate in each group.

2010-12-08 | E-GEOD-24138 | biostudies-arrayexpress

RNA-Sequencing of heart tissue obtained from cardiac specific-Dsg2-/- and wild-type (Dsg2+/+) mice at 2-weeks and 10-weeks of age

Project description:We studied how loss of the desmosome associated protein, desmoglein-2 (Dsg2), in the heart leads to Arrhythmogenic Cardiomyopathy with particular interest in the early stages of disease progression. Mice expressing the cardiac αMHC-Cre promoter were crossed with Dsg2 floxed mice in which exon 4-5 of the Dsg2 gene was flanked by loxP sites, resulting in Cre-mediated excision of Dsg2 in cardiac myocytes. Wild type Dsg2+/+ (Cre-, Dsg2flx/flx) and knockout Dsg2-/- (Cre+, Dsg2flx/flx) mice were generated. RNA-seq was performed on heart tissue obtained from wild-type and Dsg2-/- mice at 2-weeks and 10-weeks of age.

2021-07-22 | GSE153124 | GEO

Transcriptomic analysis of DSG2-W2A mouse heart tissue

Project description:Transcriptomic analysis of DSG2-W2A mouse heart tissue. In DSG2-W2A mice, adhesion of the desmosomal molecule desmoglein-2 (DSG2) is abrogated via mutation of its’ major interaction mechanism (so-called "tryptophan swap" (Harrison, Brasch et al. 2016)). Adult DSG2-W2A mut/mut mice resemble the phenotype of Arrhythmogenic Cardiomyopathy (ACM or ARVC) with biventricular fibrosis, impaired systolic output function and arrhythmia. This phenotype was present in mutant mice analysed at the age of 9 weeks compared to 5-days old hearts, which showed no morphological alterations.

2022-12-05 | GSE181868 | GEO

Electrophysiological defects in a novel patient-derived stem cell model of desmoglein-2 mutant ARVC

Project description:Here we developed a novel human induced pluripotent stem cell (hiPSC) model of ARVC to gain insight into the electrical and biomolecular effects of desmoglein-2 (DSG2) mutation in cardiomyocytes. hiPSC-derived cardiomyocytes (hiPSC-CMs) were generated from peripheral blood mononuclear cells donated by an ARVC patient with a pathogenic variant in DSG2, c.2358delA.

2021-06-06 | GSE176209 | GEO

Project description:Adenovirus serotypes small RNA sequencing

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Novel splicing and open reading frames revealed by long-read direct RNA sequencing of adenovirus transcripts

Project description:Adenovirus is a common human pathogen that relies on host cell processes for transcription and processing of viral RNA and protein production. Although adenoviral promoters, splice junctions, and cleavage and polyadenylation sites have been characterized using low-throughput biochemical techniques or short read cDNA-based sequencing, these technologies do not fully capture the complexity of the adenoviral transcriptome. By combining Illumina short-read and nanopore long-read direct RNA sequencing approaches, we mapped transcription start sites and cleavage and polyadenylation sites across the adenovirus genome. In addition to confirming the known canonical viral early and late RNA cassettes, our analysis of splice junctions within long RNA reads revealed an additional 35 novel viral transcripts. These RNAs include fourteen new splice junctions which lead to expression of canonical open reading frames (ORF), six novel ORF-containing transcripts, and fifteen transcripts encoding for messages that potentially alter protein functions through truncations or fusion of canonical ORFs. In addition, we also detect RNAs that bypass canonical cleavage sites and generate potential chimeric proteins by linking separate gene transcription units. Of these, an evolutionary conserved protein was detected containing the N-terminus of E4orf6 fused to the downstream DBP/E2A ORF. Loss of this novel protein, E4orf6/DBP, was associated with aberrant viral replication center morphology and poor viral spread. Our work highlights how long-read sequencing technologies can reveal further complexity within viral transcriptomes.

2022-08-30 | PXD034464 | Pride

The architecture of the SARS-CoV-2 RNA genome inside virion

Project description:The coronavirus disease 2019 caused by SARS-CoV-2 has led to an unprecedented health crisis. However, to date, the architecture of the viral RNA genomes inside virions have not been observed because the interiors of viral particles are not visible, even using sophisticated Cryo-electron microscopy and tomography methods. Here, we devised a virion applicable RNA in situ conformation sequencing (RIC-seq) technology, named vRIC-seq, for probing viral RNA structures in intact virions. Using vRIC-seq, we successfully generated an RNA 3D interaction map for SARS-CoV-2 and observed many topologically isolated RNA domains. Based on the map, we reconstructed the whole genome structure of SARS-CoV-2, which revealed a fascinating “unentangled globule” conformation of this RNA genome. Our secondary structure model not only faithfully captured known RNA structural elements but also identified many previously unknown long-range duplexes and higher-order junctions with apparent biological impacts. Importantly, our structural model also enabled rapid screening of potent small interfering RNAs to target vulnerable regions of the SARS-CoV-2 RNA genome to against its infections in Vero cells. Thus, beyond illustrating an innovative method for characterizing the viral RNA structures present in intact virions of potentially any RNA virus and showing how this data can be quickly exploited to develop antiviral treatments, our work offers the first empirical-data-based look at how the SARS-CoV-2 RNA genome is organized inside virions.

2021-03-25 | GSE155733 | GEO

Transcriptome Analysis of KSHV virions produced from BCBL1 and BAC36 in 293L cells

Project description:The objective of this study was to identify the viral transcripts packaged into the virion particles produced from BCBL1 cells as well as virions from 293L cells containing BAC36 BACs RNA from virions were extracted and analyzed by RNA sequencing

2014-10-16 | E-GEOD-62343 | biostudies-arrayexpress

Reovirus low-density particles package viral and cellular RNA

Project description:Packaging of segmented, double-stranded RNA viral genomes requires coordination of multiple viral proteins and RNA segments. For mammalian orthoreovirus (reovirus), evidence suggests either all ten or zero viral RNA segments are simultaneously packaged in a highly coordinated process hypothesized to exclude host RNA. Accordingly, reovirus generates genome-containing virions and “genomeless” top component particles. However, despite ostensibly lacking the genome, top component particles maintain a low level of infectivity. Whether reovirus particles can package host RNA is unknown. To gain insight into reovirus packaging potential and mechanisms, we employed next-generation RNA-sequencing to define the viral and host RNA content of purified reovirus virions and top component particles. Reovirus top component particles contained double-stranded viral RNA segments in similar proportions but at reduced levels compared to virions. Top component particles also were enriched for numerous host RNAs, especially short, non-polyadenylated transcripts, that differed by reovirus strain, independent of the viral polymerase. In contrast, virions were enriched for very few host RNAs. Collectively, these findings indicate that genome packaging into reovirus virions is exquisitely selective, while incorporation of host RNAs into top component particles is more promiscuous or differentially selective and may contribute to or result from inefficient viral RNA packaging.

2021-06-08 | GSE164270 | GEO

Profiling selective packaging of host RNA and viral RNA modification in the SARS-CoV-2 virion

Project description:Viruses package host RNAs in their virions which are associated with a range of functions in the viral life cycle. Previous transcriptomic profiling on host RNA packaging were mostly focused on retroviruses. Which host RNAs are packaged in other viruses at the transcriptome level has not been thoroughly examined. Here we apply both small RNA and large RNA sequencing of SARS-CoV-2 virions from six individual isolates in Vero cell cultures to profile packaging of host RNAs in a coronavirus and to explore SARS-CoV-2 genomic RNA modifications. We find selective packaging of specific tRNAs, tRNA fragments and signal recognition particle RNA into SARS-CoV-2 virions. Virions from all individual clones package the same set of host RNAs, suggesting a common mechanism of selective packaging. We estimate that a SARS-CoV-2 virion contains up to 1 SRP RNA and 4 tRNA molecules. We identify tRNA modification differences between the virion-packaged tRNAs and those in the uninfected host cells. Furthermore, we find subgenomic viral RNAs in the virions, and uncharacterized candidate modifications in the SARS-CoV-2 genomic RNA. Our results reveal an under-explored aspect of viral-host interaction that may be explored for viral therapeutics.

2022-03-06 | GSE182883 | GEO

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