Tuberculosis: Smart manipulation of a lethal host

Abstract

Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a global threat to human health. Development of drug resistance and co-infection with HIV has increased the morbidity and mortality caused by TB. Macrophages serve as primary defense against microbial infections, including TB. Upon recognition and uptake of mycobacteria, macrophages initiate a series of events designed to lead to generation of effective immune responses and clearance of infection. However, pathogenic mycobacteria utilize multiple mechanisms for manipulating macrophage responses to protect itself from being killed and to survive within these cells that are designed to kill them. The outcomes of mycobacterial infection are determined by several host- and pathogen-related factors. Significant advancements in understanding mycobacterial pathogenesis have been made in recent years. In this review, some of the important factors/mechanisms regulating mycobacterial survival inside macrophages are discussed.

Phospholipase C‐γ2 promotes intracellular survival of mycobacteria

“…20 PLC signalling is involved in regulation of several cellular activities due to its ability to control the cellular levels of DAG and IP3. Host macrophages are frontier cells in mounting protective immune response against mycobacteria.…”

Host phospholipase C‐γ1 impairs phagocytosis and killing of mycobacteria by J774A.1 murine macrophages

“…During the establishment of infection, pathogenic mycobacteria induce several alterations in the host cellular machinery, particularly defensive responses at various levels. 26 Several members of the host PLC family have been suggested as being involved in phagocytosis and inflammatory responses generated by macrophages following bacterial infections. 27 The hydrolysis of phosphatidylinositol 4,5-bisphosphate by PLC, activates PKC and other downstream pathways, which regulates host cellular processes such as phagocytosis.…”

Alveolar Macrophage Chromatin Is Modified to Orchestrate Host Response to Mycobacterium bovis Infection

“…Disease-causing mycobacteria, however, can persist and replicate within alveolar macrophages via a bewildering range of evolved mechanisms that subvert and interfere with host immune responses (de Chastellier, 2009;Cambier et al, 2014;Schorey and Schlesinger, 2016;Awuh and Flo, 2017). These mechanisms include recruitment of cell surface receptors on the host macrophage; blocking of macrophage phagosome-lysosome fusion; detoxification of reactive oxygen and nitrogen intermediates (ROI and RNI); harnessing of intracellular nutrient supply and metabolism; inhibition of apoptosis and autophagy; suppression of antigen presentation; modulation of macrophage signalling pathways; cytosolic escape from the phagosome; and induction of necrosis, which leads to immunopathology and shedding of the pathogen from the host (Ehrt and Schnappinger, 2009;Hussain Bhat and Mukhopadhyay, 2015;Queval et al, 2017;BoseDasgupta and Pieters, 2018;Chaurasiya, 2018;Stutz et al, 2018).…”