Immunological consequences of host signaling regulated epigenetic modification during mycobacterial pathogenesis

Abstract

Introduction: Mycobacterium tuberculosis (Mtb), the principal etiological agent of pulmonary tuberculosis (TB), continues to co-evolve with the human population making itself one of the most potent infectious killer in the modern-day world. The primary site of TB infection is the lung, wherein the tubercle bacillus is taken up by phagocytic cells such as macrophages, dendritic cells as well as neutrophils. Emerging studies have also indicated that Mtb immigrates into non-myelocytic cells to ensure itself a safe niche from the concerted immune onslaught of the host. In course of infecting the host, the bacterium attunes distinct cellular processes that would otherwise contribute to bacterial clearance viz. apoptosis, autophagy, antigen presentation, cytokine responses and lipid accumulation. Interestingly, Mtb, has been shown to initiate ectopic expression of a gamut of cellular signaling pathways, by virtue of which the immune activities of the host are tempered. The current work brings to light critical signaling nodes that are deregulated upon mycobacterial infection and demonstrates key epigenetic molecules that act downstream to these signaling intermediates to aid Mtb pathogenesis. Importantly, the study builds upon the critical role(s) of NOTCH and WNT signaling pathways during Mtb infection as well as reports the significance of SLIT-ROBO pathway that was hitherto unexplored in the context of mycobacterial pathogenesis. PART I: Elucidation of the regulation of an E3 ubiquitin ligase by Mtb-elicited epigenetic modifier. Mtb adopts diverse strategies to impede the host-mediated immunological offenses. As one of its many shrewd strategies, Mtb generates lipid-laden cells (foamy macrophages-FMs) that offer a favorable shelter for its persistence. FMs are formed by the complex regulation of influx, metabolism, storage, and mobilization of lipid molecules. The excess accumulation of lipids is often attributed to the surge in the expression of lipid influx genes with a concomitant decrease in the lipid efflux...