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Front Microbiol. 2016 Nov 7;7:1688. eCollection 2016.

Systems Biomedicine of Rabies Delineates the Affected Signaling Pathways.

Author information

1
Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences Tehran, Iran.
2
Department of Virology, School of Public Health, Tehran University of Medical Sciences Tehran, Iran.
3
Department of Physiology and Pharmacology, Pasteur Institute of Iran Tehran, Iran.
4
Department of Applied Mathematics, Faculty of Mathematical Sciences, Tarbiat Modares University Tehran, Iran.
5
Department of Immunology, School of Medicine, Tehran University of Medical Sciences Tehran, Iran.
6
Protein Chemistry and Proteomics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran Tehran, Iran.
7
WHO Collaborating Center for Reference and Research on Rabies, Pasteur Institute of Iran Tehran, Iran.
8
Faculty of New Sciences and Technology, University of TehranTehran, Iran; Department of Genetics, Evolution and Environment, UCL Genetics Institute, University College LondonLondon, UK.
9
Drug Design and Bioinformatics Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran Tehran, Iran.

Abstract

The prototypical neurotropic virus, rabies, is a member of the Rhabdoviridae family that causes lethal encephalomyelitis. Although there have been a plethora of studies investigating the etiological mechanism of the rabies virus and many precautionary methods have been implemented to avert the disease outbreak over the last century, the disease has surprisingly no definite remedy at its late stages. The psychological symptoms and the underlying etiology, as well as the rare survival rate from rabies encephalitis, has still remained a mystery. We, therefore, undertook a systems biomedicine approach to identify the network of gene products implicated in rabies. This was done by meta-analyzing whole-transcriptome microarray datasets of the CNS infected by strain CVS-11, and integrating them with interactome data using computational and statistical methods. We first determined the differentially expressed genes (DEGs) in each study and horizontally integrated the results at the mRNA and microRNA levels separately. A total of 61 seed genes involved in signal propagation system were obtained by means of unifying mRNA and microRNA detected integrated DEGs. We then reconstructed a refined protein-protein interaction network (PPIN) of infected cells to elucidate the rabies-implicated signal transduction network (RISN). To validate our findings, we confirmed differential expression of randomly selected genes in the network using Real-time PCR. In conclusion, the identification of seed genes and their network neighborhood within the refined PPIN can be useful for demonstrating signaling pathways including interferon circumvent, toward proliferation and survival, and neuropathological clue, explaining the intricate underlying molecular neuropathology of rabies infection and thus rendered a molecular framework for predicting potential drug targets.

KEYWORDS:

microarray; protein–protein interaction network; rabies; real-time PCR; signaling network; systems biology

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