ViralLink: An integrated workflow to investigate the effect of SARS-CoV-2 on intracellular signalling and regulatory pathways

Abstract

The SARS-CoV-2 pandemic of 2020 has mobilised scientists around the globe to research all aspects of the coronavirus virus and its infection. For fruitful and rapid investigation of viral pathomechanisms, a collaborative and interdisciplinary approach is required. Therefore, we have developed ViralLink: a systems biology workflow which reconstructs and analyses networks representing the effect of viruses on intracellular signalling. These networks trace the flow of signal from intracellular viral proteins through their human binding proteins and downstream signalling pathways, ending with transcription factors regulating genes differentially expressed upon viral exposure. In this way, the workflow provides a mechanistic insight from previously identified knowledge of virally infected cells. By default, the workflow is set up to analyse the intracellular effects of SARS-CoV-2, requiring only transcriptomics counts data as input from the user: thus, encouraging and enabling rapid multidisciplinary research. However, the wide-ranging applicability and modularity of the workflow facilitates customisation of viral context, a priori interactions and analysis methods. Through a case study of SARS-CoV-2 infected bronchial/tracheal epithelial cells, we evidence the functionality of the workflow and its ability to identify key pathways and proteins in the cellular response to infection. The application of ViralLink to different viral infections in a context specific manner using different available transcriptomics datasets will uncover key mechanisms in viral pathogenesis.

SARS-CoV-2 Causes a Different Cytokine Response Compared to Other Cytokine Storm-Causing Respiratory Viruses in Severely Ill Patients

“…The ongoing accumulation of patient-derived large data sets will inform the research community and clinicians of the intricacy of host/virus interactions (81). Systematic reviews such as this study should be part of an iterative process, increasing the resolution of the comparisons listed above, by continuously integrating novel data.…”

clusterProfiler 4.0: A universal enrichment tool for interpreting omics data

“…The clusterProfiler library is one of the most popular Bioconductor packages. It has been incorporated in more than 30 CRAN and Bioconductor packages ( Table S1 ), several pipelines (e.g., The Cancer Genome Atlas [TCGA] Workflow 12 and ViralLink 13 ), and online platforms (e.g., NASQAR 14 and ABioTrans 15 ).…”

Reprogramming of the intestinal epithelial-immune cell interactome during SARS-CoV-2 infection

“…Two previously established tools were employed to predict the effect of SARS-CoV-2 infection on intestinal epithelial cells: ViralLink and CARNIVAL (Liu et al, 2019;Treveil et al, 2021). Both tools, using related but distinct methods, infer causal molecular interaction networks.…”

“…Intracellular causal networks were inferred using the ViralLink pipeline, as described in (Treveil et al, 2021). Briefly, a list of expressed genes in infected immature enterocytes (originally known as "immature enterocytes 2" (MMP7+, MUC1+, CXCL1+)) from SARS-…”