Unconventional viral gene expression mechanisms as therapeutic targets

Ho, Jessica; Zhu, Zeyu; Marazzi, Ivan

doi:10.1038/s41586-021-03511-5

Cited by 31 publications

(21 citation statements)

References 192 publications

(214 reference statements)

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“…This process can stimulate the response of the innate immune system (47). GO enrichment analysis has shown that 380 genes across host clusters were enriched with functions which play essential roles in mediating cellular entry of pathogens ( e.g ., epidermal growth factor receptor (EGFR) signalling pathway (48), growth hormone receptor signalling pathway (49), mitochondrial ATP synthesis coupled electron transport (50), protein targeting to endoplasmic reticulum(51)), communication of bacteria with the host environment ( e.g ., positive regulation of establishment of protein localization(52)), control of infection ( e.g ., regulation of protein metabolic process(53)), invading pathogen ( e.g ., response to laminar fluid shear stress (54)), and co-opting host factors ( e.g ., viral gene expression (55)) that can be considered as potential targets in designing antibacterial therapies. Enriched functions were mostly observed at 24h and 4h pi in the host and pathogen, respectively, with mainly downregulated expression (Supplementary Table).…”

Section: Resultsmentioning

confidence: 99%

dSeqSb: A systems biology approach to decipher dynamics of host-pathogen interactions using temporal dual RNA-seq data

Dinarvand

Koch

Mouiee

et al. 2022

Preprint

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Infection triggers a dynamic cascade of reciprocal events between host and pathogen wherein the host activates complex mechanisms to recognise and kill pathogens while the pathogen adjusts its virulence and fitness to avoid eradication by the host. The interaction between the pathogen and the host results in large-scale changes in gene expression in both organisms. Dual RNA-seq, the simultaneous detection of host and pathogen transcripts, has become a leading approach to unravel complex molecular interactions between the host and the pathogen and is particularly informative for intracellular organisms. The amount of in vitro and in vivo dual RNA-seq data is rapidly growing which demands computational pipelines to effectively analyse such data. In particular, holistic, systems-level, and temporal analyses of dual RNA-seq data are essential to enable further insights into the host-pathogen transcriptional dynamics and potential interactions. Here, we developed an integrative network-driven bioinformatics pipeline, dRNASb, a systems biology-based computational pipeline to analyse temporal transcriptional clusters, incorporate molecular interaction networks (e.g., protein-protein interactions), identify topologically and functionally key transcripts in host and pathogen, and associate host and pathogen temporal transcriptome to decipher potential between-species interactions. The pipeline is applicable to various dual RNA-seq data from different species and experimental conditions. As a case study, we applied dRNASb to analyse temporal dual RNA-seq data of Salmonella-infected human cells, which enabled us to uncover genes contributing to the infection process and their potential functions and to identify potential host-pathogen interactions between host and pathogen genes. Overall, dRNASb has the potential to identify key genes involved in bacterial growth or host defence mechanisms for future uses as therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

dSeqSb: A systems biology approach to decipher dynamics of host-pathogen interactions using temporal dual RNA-seq data

Dinarvand

Koch

Mouiee

et al. 2022

Preprint

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“…We identified EXOSC2 because it interacts with the SARS-CoV-2 polymerase (Gordon et al 2020). Interaction between the host RNA exosome and the viral RNA polymerase is important for viral replication for influenza A virus (IAV) and Lassa virus (Ho et al 2021). These viruses do not encode their own capping enzymes and so take advantage of host caps which are a byproduct of RNA degradation by the RNA exosome.…”

Section: Discussionmentioning

confidence: 99%

Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication

Moll

Odon

Harvey

et al. 2022

Preprint

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New therapeutic targets are a valuable resource in the struggle to reduce the morbidity and mortality associated with the COVID-19 pandemic, caused by the SARS-CoV-2 virus. Genome-wide association studies (GWAS) have identified risk loci, but some loci are associated with co-morbidities and are not specific to host-virus interactions. Here, we identify and experimentally validate a link between reduced expression of EXOSC2 and reduced SARS-CoV-2 replication. EXOSC2 was one of 332 host proteins examined, all of which interact directly with SARS-CoV-2 proteins; EXOSC2 interacts with Nsp8 which forms part of the viral RNA polymerase. Lung-specific eQTLs were identified from GTEx (v7) for each of the 332 host proteins. Aggregating COVID-19 GWAS statistics for gene-specific eQTLs revealed an association between increased expression of EXOSC2 and higher risk of clinical COVID-19 which survived stringent multiple testing correction. EXOSC2 is a component of the RNA exosome and indeed, LC-MS/MS analysis of protein pulldowns demonstrated an interaction between the SARS-CoV-2 RNA polymerase and the majority of human RNA exosome components. CRISPR/Cas9 introduction of nonsense mutations within EXOSC2 in Calu-3 cells reduced EXOSC2 protein expression, impeded SARS-CoV-2 replication and upregulated oligoadenylate synthase (OAS) genes, which have been linked to a successful immune response against SARS-CoV-2. Reduced EXOSC2 expression did not reduce cellular viability. OAS gene expression changes occurred independent of infection and in the absence of significant upregulation of other interferon-stimulated genes (ISGs). Targeted depletion or functional inhibition of EXOSC2 may be a safe and effective strategy to protect at-risk individuals against clinical COVID-19.

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“…Viral polymerases recognize key features within 5’-UTRs to begin transcription, presenting another key function of these regions [ 64 , 65 ]. Thus, UTRs within viral RNAs may be potential future antiviral therapeutic targets that not only serve to block translation but may also curb continuous replication of the viral genome by additionally inhibiting RNA transcription [ 66 , 67 ].…”

Section: Viral 5’-utrs As Antiviral Therapeutic Targetsmentioning

confidence: 99%

Short and Sweet: Viral 5`-UTR as a Canonical and Non-Canonical Translation Initiation Switch

Trainor

Shcherbik

2021

Journal of Cellular Immunology

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Unconventional viral gene expression mechanisms as therapeutic targets

Cited by 31 publications

References 192 publications

dSeqSb: A systems biology approach to decipher dynamics of host-pathogen interactions using temporal dual RNA-seq data

dSeqSb: A systems biology approach to decipher dynamics of host-pathogen interactions using temporal dual RNA-seq data

Low expression of EXOSC2 protects against clinical COVID-19 and impedes SARS-CoV-2 replication

Short and Sweet: Viral 5`-UTR as a Canonical and Non-Canonical Translation Initiation Switch

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