Convergent perturbation of the human domain-resolved interactome by viruses and mutations inducing similar disease phenotypes

Abstract

An important goal of systems medicine is to study disease in the context of genetic and environmental perturbations to the human interactome network. For diseases with both genetic and infectious contributors, a key postulate is that similar perturbations of the human interactome by either disease mutations or pathogens can have similar disease consequences. This postulate has so far only been tested for a few viral species at the level of whole proteins. Here, we expand the scope of viral species examined, and test this postulate more rigorously at the higher resolution of protein domains. Focusing on diseases with both genetic and viral contributors, we found significant convergent perturbation of the human domain-resolved interactome by endogenous genetic mutations and exogenous viral proteins inducing similar disease phenotypes. Pan-cancer, pan-oncovirus analysis further revealed that domains of human oncoproteins either physically targeted or structurally mimicked by oncoviruses are enriched for cancer driver rather than passenger mutations, suggesting convergent targeting of cancer driver pathways by diverse oncoviruses. Our study provides a framework for high-resolution, network-based comparison of various disease factors, both genetic and environmental, in terms of their impacts on the human interactome.

A Structure-Informed Atlas of Human-Virus Interactions

“…We also identified 173 human proteins, predicted to interact with at least 100 viruses, enriched for processes related to immunity, virus infection, and functions known to be important during viral replication (e.g., regulation of cell cycle and membrane organization), providing insights into cellular processes broadly relevant for virus-human dynamics (Figures S3C and S3D). In agreement with recent findings (Chen and Xia, 2019), we find that these proteins are also enriched for virally implicated genetic diseases. The identification of pan-viral factors that converge around common cellular pathways is made possible both by the comprehensive nature of the P-HIPSTer database and by the large number of interactions detected by structural homology.…”

“…Positively selected genes are of particular interest, as they represent key adaptive sweeps that have been shaped by environmental pressures, including those imposed by viruses. Analysis of the 45 virus-interacting proteins under positive selection (with mean DN/DS values >1) reveals that they are highly enriched for functions and diseases related to viral infection, as well as adaptive and innate immune responses (Figure 6B)-a similar relationship was recently described (Chen and Xia, 2019). Reflecting their central role in initiating and mediating responses to a variety of pathogens, regulators of immunity are also enriched among the 329 positively selected genes not predicted to interact with viruses.…”

RETRACTED: Rationale and Criteria for a COVID-19 Model Framework

“…Recent advances in systems biology spawned the view of human disease as a manifestation of genetic and environmental perturbations to the human interactome, a key postulate being that similar perturbation patterns lead to similar disease phenotypes [ 7 ]. However, infectious diseases are extremely complex, as the dynamics of infection into the host could be influenced by the pathogen and the host response could induce adaptation events into the pathogen [ 8 , 9 ].…”

Host-Directed Antiviral Therapy

“…Kinases are implicated in various physiological processes to maintain cellular homeostasis, and their dysregulation could result in pathology. Infections by pathogens, including viral infections, are also associated with perturbation of the "kinome" (98,99). Each step of the virus replication cycle can be regulated by multiple kinases (100)(101)(102).…”