The two-stage molecular scenery of SARS-CoV-2 infection with implications to disease severity: An in-silico quest

Abstract

Introduction: The two-stage molecular profile of the progression of SARS-CoV-2 (SCOV2) infection is explored in terms of five key biological/clinical questions: (a) does SCOV2 exhibits a two-stage infection profile? (b) SARS-CoV-1 (SCOV1) vs. SCOV2: do they differ? (c) does and how SCOV2 differs from Influenza/INFL infection? (d) does low viral-load and (e) does COVID-19 early host response relate to the two-stage SCOV2 infection profile? We provide positive answers to the above questions by analyzing the time-series gene-expression profiles of preserved cell-lines infected with SCOV1/2 or, the gene-expression profiles of infected individuals with different viral-loads levels and different host-response phenotypes.

Methods: Our analytical methodology follows an in-silico quest organized around an elaborate multi-step analysis pipeline including: (a) utilization of fifteen gene-expression datasets from NCBI's gene expression omnibus/GEO repository; (b) thorough designation of SCOV1/2 and INFL progression stages and COVID-19 phenotypes; (c) identification of differentially expressed genes (DEGs) and enriched biological processes and pathways that contrast and differentiate between different infection stages and phenotypes; (d) employment of a graph-based clustering process for the induction of coherent groups of networked genes as the representative core molecular fingerprints that characterize the different SCOV2 progression stages and the different COVID-19 phenotypes. In addition, relying on a sensibly selected set of induced fingerprint genes and following a Machine Learning approach, we devised and assessed the performance of different classifier models for the differentiation of acute respiratory illness/ARI caused by SCOV2 or other infections (diagnostic classifiers), as well as for the prediction of COVID-19 disease severity (prognostic classifiers), with quite encouraging results.

Results: The central finding of our experiments demonstrates the down-regulation of type-I interferon genes (IFN-1), interferon induced genes (ISGs) and fundamental innate immune and defense biological processes and molecular pathways during the early SCOV2 infection stages, with the inverse to hold during the later ones. It is highlighted that upregulation of these genes and pathways early after infection may prove beneficial in preventing subsequent uncontrolled hyperinflammatory and potentially lethal events.

Discussion: The basic aim of our study was to utilize in an intuitive, efficient and productive way the most relevant and state-of-the-art bioinformatics methods to reveal the core molecular mechanisms which govern the progression of SCOV2 infection and the different COVID-19 phenotypes.

Keywords: COVID-19; SARS-CoV-2; diagnostic and prognostic classifier models; differential expression analysis; machine learning; pathway enrichment analysis.