Network analysis of host-pathogen protein interactions in microbe induced cardiovascular diseases

Abstract

Large-scale visualization and analysis of HPIs involved in microbial CVDs can provide crucial insights into the mechanisms of pathogenicity. The comparison of CVD associated HPIs with the entire set of HPIs can identify the pathways specific to CVDs. Therefore, topological properties of HPI networks in CVDs and all pathogens was studied using Cytoscape3.5.1. Ontology and pathway analysis were done using KOBAS 3.0. HPIs of Papilloma, Herpes, Influenza A virus as well as Yersinia pestis and Bacillus anthracis among bacteria were predominant in the whole (wHPI) and the CVD specific (cHPI) network. The central viral and secretory bacterial proteins were predicted virulent. The central viral proteins had higher number of interactions with host proteins in comparison with bacteria. Major fraction of central and essential host proteins interacts with central viral proteins. Alpha-synuclein, Ubiquitin ribosomal proteins, TATA-box-binding protein, and Polyubiquitin-C &B proteins were the top interacting proteins specific to CVDs. Signaling by NGF, Fc epsilon receptor, EGFR and ubiquitin mediated proteolysis were among the top enriched CVD specific pathways. DEXDc and HELICc were enriched host mimicry domains that may help in hijacking of cellular machinery by pathogens. This study provides a system level understanding of cardiac damage in microbe induced CVDs.

Keywords: HP-PPIs; Network; central; immune; pathway.

Fig. 1

A layout of host-pathogen protein-protein interaction networks. a) The schematic of wHPI network with distribution of pathogens shown in blue circular shapes and their respective numbers of proteins in orange pentagonal shapes interacting with total number of host proteins shown in light red ellipse. b) The schematic of cHPI network with distribution of pathogens shown in red circular shapes and their respective numbers of proteins in purple pentagonal shapes interacting with total number of host proteins shown in green ellipse.

Fig. 2

The layout of the cHPI network. The network shows the host-pathogen interactions between host and pathogen proteins. On the right-hand side there is zoomed version of a small portion of the large network.

Fig. 3

The degree distribution graphs of the network. The scatter plot of nodes based on their degree values is depicted in the graphs. a) The node vs degree graph of the wHPI network. b) The node vs degree graph of the cHPI network. The red line indicates the fitting of power law in both the networks.

Fig. 4

Gene ontology analysis of host proteins. a) The bar plot of enriched biological processes of host proteins; b) The bar plot enriched molecular functions of host proteins; c) The bar plot of enriched cellular components of host proteins. The blue bar represents the number of proteins; the green bar represents the reference p-value, and the red bar represents the p-value of the respective ontology term.

Fig. 5

Gene ontology analysis of pathogen proteins. a) The bar plot of enriched biological processes of pathogen proteins; b) The bar plot enriched molecular functions of pathogen proteins; c) The bar plot of enriched cellular components of pathogen proteins. The blue bar represents the number of proteins; the green bar represents the reference p-value, and the red bar represents the p-value of the respective ontology term.

Fig. 6

A Venn diagram to see overlapping of number of enriched pathways. The purple ellipse represents the total number of enriched pathways of cHPI network; the yellow ellipse represents the total number of enriched pathways involved in viral myocarditis related GEO dataset (GSE150392); the green ellipse represents the total number of enriched pathways present in pericarditis related GEO dataset (GSE122903) and the pink ellipse represents the total number of enriched pathways present in endocarditis related GEO dataset (GSE29161).