Viral Perturbations of Host Networks Reflect Disease Etiology

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. Many “virally implicated human diseases” - diseases for which there is scientific consensus of viral involvement - are associated with genetic alterations in particular disease susceptibility genes. 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 (local impact hypothesis). For representative EBV- and HPV16- implicated diseases, genes in the neighborhood of viral targets in the host interactome have significantly shifted expression levels in virally implicated disease tissues, in line with the local impact hypothesis. The viral neighborhoods in the host interactome, along with their disease associations, defined as “viral disease networks”, contain connections known to be informative upon disease mechanisms as well as diseases whose associations with viruses are not yet known. 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. Exogenous expression of HPV viral proteins in a human cell line offered evidence for a novel disease pathway that links HPV to Fanconi anemia.