Network controllability analysis of intracellular signalling reveals viruses are actively controlling molecular systems

Ravindran, V., Nacher, J. C., Akutsu, T., Ishitsuka, M., Osadcenco, A., Sunitha, V., Bagler, G., Schwartz, J.-M. and Robertson, D. L. (2019) Network controllability analysis of intracellular signalling reveals viruses are actively controlling molecular systems. Scientific Reports, 9, 2066. (doi:10.1038/s41598-018-38224-9) (PMID:30765882) (PMCID:PMC6375943)

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Abstract

In recent years control theory has been applied to biological systems with the aim of identifying the minimum set of molecular interactions that can drive the network to a required state. However, in an intra-cellular network it is unclear how control can be achieved in practice. To address this limitation we use viral infection, specifically human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV), as a paradigm to model control of an infected cell. Using a large human signalling network comprised of over 6000 human proteins and more than 34000 directed interactions, we compared two states: normal/uninfected and infected. Our network controllability analysis demonstrates how a virus efficiently brings the dynamically organised host system into its control by mostly targeting existing critical control nodes, requiring fewer nodes than in the uninfected network. The lower number of control nodes is presumably to optimise exploitation of specific sub-systems needed for virus replication and/or involved in the host response to infection. Viral infection of the human system also permits discrimination between available network-control models, which demonstrates that the minimum dominating set (MDS) method better accounts for how the biological information and signals are organised during infection by identifying most viral proteins as critical driver nodes compared to the maximum matching (MM) method. Furthermore, the host driver nodes identified by MDS are distributed throughout the pathways enabling effective control of the cell via the high ‘control centrality’ of the viral and targeted host nodes. Our results demonstrate that control theory gives a more complete and dynamic understanding of virus exploitation of the host system when compared with previous analyses limited to static single-state networks.

Item Type:Articles
Additional Information:VR was supported by the Inspire Fellowship from the Department of Science and Technology (DST/INSPIRE/ IF120809), the University of Manchester from a visiting researchers fund and is now supported by the Royal Society-SERB International Newton Fellowship (NF171560). VR, VS and GB thank DA-IICT for support, and GB also thanks IIIT-Delhi for support. DLR was partially supported by the MRC (MC_UU_1201412). DLR and JCN thank the Royal Society for an International Exchange grant (IE160248). JCN was partially supported by JSPS KAKENHI (18K11535). TA was partially supported by JSPS KAKENHI (18H04113). JCN and TA were also supported in part by Research Collaboration Projects of the Institute for Chemical Research, Kyoto University.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ravindran, Dr Vandana and Robertson, Professor David
Authors: Ravindran, V., Nacher, J. C., Akutsu, T., Ishitsuka, M., Osadcenco, A., Sunitha, V., Bagler, G., Schwartz, J.-M., and Robertson, D. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Scientific Reports
Publisher:Nature Research
ISSN:2045-2322
ISSN (Online):2045-2322
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Scientific Reports 9: 2066
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
UNSPECIFIEDUNSPECIFIEDUNSPECIFIEDUNSPECIFIEDMedical Research Council (MRC)12014/12UNSPECIFIED