Network Analysis to Identify Key Proteins and Pathways Targeted During Herpesvirus Infection

Zachary S. Wallace

Mentor: Dr. Richard H. Scheuermann, Department of Bioinformatics, J. Craig Venter Institute

Date/Time: August 27, 2019 at 2pm

Location: Room 1300, Harris Building

Background: As a virus infects a host cell, a system of hundreds of host and viral protein interactions is established, targeting specific host proteins that are part of biological pathways critical for virus replication. Identifying key target proteins and determining the biological pathways they are part of is vital for understanding how these viruses operate and can be used to develop novel antiviral treatments. Thanks to ongoing high throughput experimentation and public bioinformatics databases, the analysis of host-virus protein-protein interactions (PPI) is an emerging field in biology.

Methods: We compared host-virus PPIs among Human Herpesvirus 1 (aka HSV1), 4 (EBV), and 5 (CMV). The host-virus PPI data were obtained from the Host-Pathogen Interaction Database (HPIDB; http://hpidb.igbb.msstate.edu).  In order to gain a comprehensive view of the pathways targeted during infection, we started by decomposing a complete human interactome (no pathogen proteins), acquired from the database Mentha (http://mentha.uniroma2.it), into modules using the Louvain community detection algorithm and then used the host-virus PPI data to determine which host modules were attacked by virus proteins.  We then applied GO Biological Process (BP) enrichment calculations to the targeted modules and determined the pathways attacked by these viruses.  Additionally, we computed degree centrality, betweenness centrality, eigenvector centrality, and closeness centrality measures of the target host proteins in each module to evaluate if the viruses were interacting with “central proteins”.  To define a protein as central, we established statistical criteria for determining if the target proteins showed significant centrality measures.

Results: After clustering the human interactome using Louvain, we found that 270 of 388 modules were targeted by one of the three herpesviruses. Altogether, there were 31 modules commonly targeted by all three viruses, with enriched GO BPs including chromatin organization, ribosome biogenesis, RNA splicing, and endocytosis.  We discovered that the six proteins HNRNPA1, RUVBL1, RBB4, USP7, DAXX, and XRCC5 were commonly targeted by all three viruses and that all six were central proteins based on our statistical criteria. Additionally, over half of all targeted modules for each virus contained a targeted central protein.

Conclusion: All three human herpesviruses target the central biological processes of transcription, DNA repair, gene expression, cell cycle, and immune response. For many of these targeted pathways, the viruses appear to attack a protein that occupies a central topological position within the host protein interaction modules, including modules attacked by only one virus protein. This could signify that viruses have evolved to recognize central proteins in a biological pathway in order to perturb key cellular processes in the most efficient way possible. However, the question as to why the viruses do not attack central proteins of all targeted pathways remains unknown, but the authors hypothesize that viruses need to be selective in how they attack certain pathways in order to successfully take over the cell and not destroy it too early on in the infection process.