Host-Microbe Interactions in Manifestation of Tuberculosis: A System Biology Study in Implicated Compartments

Abstract

Mycobacterium tuberculosis (Mtb) has been a dilemma for over a century. Thus the bacteria-host interactions seem to be implicated in the manifestation of the disease. Here, the behavioral activities of the Mtb and host responses were evaluated in this system biology analyses, according to the compartmental immune responses in the lung and local lymph node. Differential expression analyses were conducted between tuberculosis (TB) and the healthy group in the aforementioned compartments, to identify the hub genes and functional gene ontology (GO) terms, using KEGG, Enrichr and DAVID databases. The different phases of immune responses against Mtb occur in three compartments, lung, local lymph nodes and blood. Due to the occurrence of hypoxia within granuloma in the lung, angiogenesis was increased despite the HIF1- down-regulation via inhibition of EP300 and HDAC1. Proliferation by MYC, CDK2 and NF-{kappa}B pathways activated in the granuloma, while at the same time apoptosis was induced by P53 activation, and PI3K/Akt inhibited P53 in the lymph node. Furthermore, DNA damages suppressed by the over-expression of BRCA1, CDK1 and BCR/ABL in the lymph node, as well as FBXO6, CDK2 and CDC5A in both compartments. In the lymph node, RTK (EGFR) and calmodulin, the consequent NFAT formation and Erk/MAPK pathway down-regulated and suppressed Th1 cell activation and differentiation. Inflammation was induced in both compartments, but the antigen (Ag) presentation was suppressed through the XPO1 suppression and ubiquitination. More studies in Mtb-host interactions are needed to specify the effective mechanisms for reducing this re-emerging life-threatening disease. ImportanceTuberculosis (TB) is one of the most widespread reemerging infectious diseases in the world, which has remained a global health problem. Approximately, 10 million people are infected with Mycobacterium tuberculosis (Mtb), causing 1.2 million deaths every year. Therefore, interactions between the host and the pathogen in Mtb infection are a major challenge for the control of the disease. Typically, there are thousands of genes and ten times more interactions between any stages of the conflicts. This urged us to bring "systemic approaches" for a better understanding of such highly orchestrated systems. A holistic view of the Mtb-host interaction paves the way for a higher insight into the biology of the organism, as well as rationale solutions for the design of therapeutic agents. This study specifies the nominated disease-related genes and related signaling pathways in the pathogenesis of TB in two different compartments, lung and lymph node.