Looking for pathways related to COVID-19 phenotypes: Confirmation of pathogenic mechanisms by SARS-CoV-2 - Host interactome

Abstract

In the last months, many studies have clearly described several mechanisms of SARS−CoV−2 infection at cell and tissue level. Host conditions and comorbidities were identified as risk factors for severe and fatal disease courses, 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 on published PPI, using an explorative algorithm (Random Walk with Restart) triggered by all the 28 proteins of SARS−CoV−2, or each single viral protein one−by−one. The functional analysis for all proteins, linked to many aspects of COVID−19 pathogenesis, allows to identify the subcellular districts, where SARS−CoV−2 proteins seem to be distributed, while in each interactome built around one single viral protein, a different response was described, underlining as ORF8 and ORF3a modulated cardiovascular diseases and pro-inflammatory pathways, respectively. Finally, an explorative network-based approach was applied to Bradykinin Storm, highlighting a possible direct action of ORF3a and NS7b to enhancing this condition. This network-based model for 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.

RETRACTED: Rationale and Criteria for a COVID-19 Model Framework

“…The virus–host interactome is a network of virus–human protein–protein interactions (PPIs) that can help understanding COVID-19 mechanisms. It can be expanded by merging virus-host PPI data with human PPI and protein data to discover clusters of interactions indicating human mechanisms and pathways affected by SARS-CoV-2 [ 11 , 16 ].…”

“…Computational modeling can contribute to a deeper understanding of relevant chemical and biological phenomena based on their underlying mechanisms, applying network-based model of viral–host interaction [ 10 , 11 , 12 ]. Simulations of models can help investigating a complete biological process instead of considering smaller segments or aspects, detailing a segment of a process.…”

The mechanism of SARS-CoV-2 nucleocapsid protein recognition by the human 14-3-3 proteins

“…In addition to their high abundance in many tissues susceptible to SARS-CoV-2 infection (Fig. 1), 14-3-3 proteins were reported as one of nine key host proteins during SARS-CoV-2 infection [47], indicating their potential association with viral proteins.…”

Modulating Protein–Protein Interactions by Cyclic and Macrocyclic Peptides. Prominent Strategies and Examples

“…In the time of the dreadful pandemic, cyclic and macrocyclic peptides could also play an important role in the search for antiviral agents. It is now fairly well established that the virus spike protein interacts with ACE2 and neuropilin-1 receptors through protein–protein interactions [ 103 , 104 , 105 ]. Similarly, the main protease (Mpro) of SARS-CoV-2, the causative etiological agent of COVID-19, is a transient homodimer indispensable for processing virus essential proteins [ 106 ].…”