Looking for pathways related to COVID-19: confirmation of pathogenic mechanisms by SARS-CoV-2\u2013host interactome

Francesco Messina,Giuseppe Ippolito,Markus Maeurer,Franco Locatelli,Antonio Zoccoli,Maria R Capobianchi,Francesco Nicola Lauria,Rafick-Pierre Sekaly,Alimuddin Zumla,Emanuela Giombini,Chiara Montaldo,Ashish Arunkumar Sharma

doi:10.1038/s41419-021-03881-8

Abstract

In the last months, many studies have clearly described several mechanisms of SARS-CoV-2 infection at cell and tissue level, but the mechanisms of interaction between host and SARS-CoV-2, determining the grade of COVID-19 severity, are still unknown. We provide a network analysis on protein–protein interactions (PPI) between viral and host proteins to better identify host biological responses, induced by both whole proteome of SARS-CoV-2 and specific viral proteins. A host-virus interactome was inferred, applying an explorative algorithm (Random Walk with Restart, RWR) triggered by 28 proteins of SARS-CoV-2. The analysis of PPI allowed to estimate the distribution of SARS-CoV-2 proteins in the host cell. Interactome built around one single viral protein allowed to define a different response, underlining as ORF8 and ORF3a modulated cardiovascular diseases and pro-inflammatory pathways, respectively. Finally, the network-based approach highlighted a possible direct action of ORF3a and NS7b to enhancing Bradykinin Storm. This network-based representation of SARS-CoV-2 infection could be a framework for pathogenic evaluation of specific clinical outcomes. We identified possible host responses induced by specific proteins of SARS-CoV-2, underlining the important role of specific viral accessory proteins in pathogenic phenotypes of severe COVID-19 patients.

Highlights

Introduction Whilst COVID19 predominantly affects the respiratory system, it is a multisystem disease, with a wide spectrum of clinical presentations from asymptomatic, mild and moderate, to severe, fulminant disease[1]
A wellknown process is the cleavage of S protein by FURIN on the cell membrane, which lead to the split S protein into two subunits, S1 and S2, which the last can interact with ACE2
To further dissect the interactions with the entire proteome of SARS-CoV-2 and to better understand which pathways could be involved, enrichment analysis was carried out on proteins reported in the interactome, using WikiPathways and Kyoto Encyclopaedia of Genes and Genomes (KEGG) databases

Summary

Introduction

19 predominantly affects the respiratory system, it is a multisystem disease, with a wide spectrum of clinical presentations from asymptomatic, mild and moderate, to severe, fulminant disease[1]. Host conditions and comorbidities (age, obesity, diabetes, hypertension, organ damages, inflammation and coagulation dysfunctionality), represented risk factors for severe and fatal disease courses[2], but the mechanisms of host-SARS-CoV-2 interaction, Recently, several studies described many mechanisms of SARS-CoV-2 infection at cell and tissue level. It was observed that the replication of SARS-CoV-2, as well as all +RNA viruses, occurs in the cytoplasm of the host cell, inducing a membrane rearrangement of rough endoplasmic reticulum (ER) membranes into doublemembrane vesicles[3,4].

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Conclusion