Systems Biomedicine of Rabies Delineates the Affected Signaling Pathways

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.

Can We Assume the Gene Expression Profile as a Proxy for Signaling Network Activity?

“…Different layers of gene regulation need to be considered for each gene pair when inferring causal relationships between a pair of genes. Previously, we also demonstrated the association of altered expression with the signaling circuits in chronic obstructive pulmonary disease [41] and rabies infection [42] as case studies.…”

Natural Infection with Rabies Virus: A Histopathological and Immunohistochemical Study of Human Brains

“…Apoptosis plays an important biological role in the development and homeostasis of cell populations, as well as in the pathogenesis and expression of many disease processes [35]. Apoptosis has been proposed to be the principal cause of neuronal death [11], limiting the spread of viruses [36–38]. An important regulatory event in the apoptotic process is the activation of caspases, a family of cysteine proteases [39].…”

“…Patients eventually die of circulatory insufficiency, cardiac arrest as well as respiratory failure [10]. However, the exact mechanisms underlying RV infection in human and the pathogenesis of rabies are not completely understood [11]. To develop an effective therapeutic approach, it is important to fully understand the mechanism by which rabies causes lethal neurological disease.…”

Unsupervised Learning and Multipartite Network Models: A Promising Approach for Understanding Traditional Medicine

“…For example, in protein-protein interaction networks, clique-based clustering was used to detect protein complexes ( Altaf-Ul-Amin et al., 2006 ; Phan and Sternberg, 2012 ; Jafari et al., 2013 ). Hierarchical clustering was utilized to identify signaling cascades or metabolic pathways ( Guimera and Amaral, 2005 ; Koch and Ackermann, 2013 ; Azimzadeh Jamalkandi et al., 2016 ). Also, according to the local topological features of biological networks, clustering methods are commonly used to predict cellular co-localization and co-expressed gene regulatory mechanisms ( Dittrich et al., 2008 ; Amiri et al., 2013 ; Mitra et al., 2013 ).…”