Viral Perturbations of Host Networks Reflect Disease Etiology

Natali Gulbahce,Danielle Byrdsong,Amy Baldwin,Frederick P Roth,Nicolas Simonis,James A Decaprio,Marc Vidal,Elliott Kieff,Miranda Grace,Megha Padi,Deok-Sun Lee,Bo Zhao,Karl Münger,Karin Hellner,Amélie Dricot,Han Yan,Renee Rubio,Michael E Cusick,Orit Rozenblatt-Rosen,Nicholas A Christakis,David E Hill,John Quackenbush,Michael A Calderwood,Kyung-Won Huh,Jessica C Mar,Pascal Braun,Jarrod A Marto,Rachel Franchi,Alyce A Chen ,S Balaji ,Jennifer Roecklein‐Canfield ,Albert‐László Barabási

doi:10.1371/journal.pcbi.1002531

Abstract

Many human diseases, arising from mutations of disease susceptibility genes (genetic diseases), are also associated with viral infections (virally implicated diseases), either in a directly causal manner or by indirect associations. Here we examine whether viral perturbations of host interactome may underlie such virally implicated disease relationships. Using as models two different human viruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), we find that host targets of viral proteins reside in network proximity to products of disease susceptibility genes. Expression changes in virally implicated disease tissues and comorbidity patterns cluster significantly in the network vicinity of viral targets. The topological proximity found between cellular targets of viral proteins and disease genes was exploited to uncover a novel pathway linking HPV to Fanconi anemia.

Highlights

Functional interactions between cellular targets of viral proteins and disease susceptibility genes [1,2,3,4,5] might play key roles in disease etiology
We proposed and demonstrated that for two human viruses, Epstein-Barr virus and human papillomavirus, topological proximity should exist between host targets of viruses and genes associated with virally implicated diseases on host interactome networks
We prioritized these diseases for their candidacy as potential virally implicated diseases based on network topology, and benchmarked this prioritization of candidate diseases using relative risk measurement which depicts population-based clinical associations between candidate diseases and viral infection

Summary

Introduction

Functional interactions between cellular targets of viral proteins and disease susceptibility genes [1,2,3,4,5] might play key roles in disease etiology. We formulate a local impact hypothesis, stating that diseases that can be either genetic or virally implicated can be better understood from a network perspective [6] By this hypothesis the products of disease susceptibility genes should reside in the network vicinity of the corresponding viral targets [7,8]. To test this hypothesis we focused on Epstein-Barr virus (EBV) and human papillomavirus (HPV) type 16, two human viruses that differ in their host tropism, genome and proteome size, and disease etiology. We could identify a viral disease module for EBV and HPV, representing a subnetwork of the interactome that contains key mechanistic pathways responsible for the observed virus-disease associations. The systematic network-based framework we applied works to decipher the interplay between viruses and disease phenotypes

Methods

Results

Discussion

Conclusion