Understanding Human-Virus Protein-Protein Interactions Using a Human Protein Complex-Based Analysis Framework

Abstract

Computational analysis of human-virus protein-protein interaction (PPI) data is an effective way toward systems understanding the molecular mechanism of viral infection. Previous work has mainly focused on characterizing the global properties of viral targets within the entire human PPI network. In comparison, how viruses manipulate host local networks (e.g., human protein complexes) has been rarely addressed from a computational perspective. By mainly integrating information about human-virus PPIs, human protein complexes, and gene expression profiles, we performed a large-scale analysis of virally targeted complexes (VTCs) related to five common human-pathogenic viruses, including influenza A virus subtype H1N1, human immunodeficiency virus type 1, Epstein-Barr virus, human papillomavirus, and hepatitis C virus. We found that viral targets are enriched within human protein complexes. We observed in the context of VTCs that viral targets tended to have a high within-complex degree and to be scaffold and housekeeping proteins. Complexes that are essential for viral propagation were simultaneously targeted by multiple viruses. We characterized the periodic expression patterns of VTCs and provided the corresponding candidates that may be involved in the manipulation of the host cell cycle. As a potential application of the current analysis, we proposed a VTC-based antiviral drug target discovery strategy. Finally, we developed an online VTC-related platform known as VTcomplex (http://zzdlab.com/vtcomplex/index.php or http://systbio.cau.edu.cn/vtcomplex/index.php). We hope that the current analysis can provide new insights into the global landscape of human-virus PPIs at the VTC level and that the developed VTcomplex will become a vital resource for the community. IMPORTANCE Although human protein complexes have been reported to be directly related to viral infection, previous studies have not systematically investigated human-virus PPIs from the perspective of human protein complexes. To the best of our knowledge, we have presented here the most comprehensive and in-depth analysis of human-virus PPIs in the context of VTCs. Our findings confirm that human protein complexes are heavily involved in viral infection. The observed preferences of virally targeted subunits within complexes reflect the mechanisms used by viruses to manipulate host protein complexes. The identified periodic expression patterns of the VTCs and the corresponding candidates could increase our understanding of how viruses manipulate the host cell cycle. Finally, our proposed conceptual application framework of VTCs and the developed VTcomplex could provide new hints to develop antiviral drugs for the clinical treatment of viral infections.

Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2

“…Viruses (including HCoV) require host cellular factors for successful replication during infection 1 . Systematic identification of virus-host protein-protein interactions (PPIs) offers an effective way toward elucidating the mechanisms of viral infection 15,16 . Subsequently, targeting cellular antiviral targets, such as virus-host interactome, may offer a novel strategy for the development of effective treatments for viral infections 1 , including SARS-CoV 17 , MERS-CoV 17 , Ebola virus 18 , and Zika virus 14,[19][20][21] .…”

Prediction of SARS-CoV interaction with host proteins during lung aging reveals a potential role for TRIB3 in COVID-19

“…The conserved evolutionary relationship between the 2019 novel SARS-CoV-2 and SARS-CoV 9 opens up the possibility to explore the relationships between these human coronaviruses (HCoVs) in public databases. Computational predictions of SARS-CoV-human protein-protein interactions (PPIs) may identify mechanisms of viral infection and drug targets [9][10][11] . In this context, the Genotype-Tissue Expression (GTEx) database 12,13 has provided insights into age-related genes 14,15 and, associated with single-cell transcriptomics, could predict SARS-CoV-2-PPIs in aging lungs.…”

Pathway enrichment analysis of virus-host interactome and prioritization of novel compounds targeting the spike glycoprotein receptor binding domain–human angiotensin-converting enzyme 2 interface to combat SARS-CoV-2

“…The host-SARS-CoV interaction is established through various strategies and various host cellular mechanisms are utilized by the virus for its successful multiplication during the infection (Zumla et al., 2020). The mechanism of the viral infection can be elucidated systematically by identifying the protein-protein interactions (PPIs) during the virus-host interplay (Yang et al., 2019 ; Chuang et al., 2019). Viruses induce malfunction of the host cell by mimicking interacting domains of the host proteins, thus manipulating the signalling networks and cellular responses for their benefit (Pawson & Warner, 2007 ).…”