Macrophage Takeover and the Host–bacilli interplay During Tuberculosis

Abstract

Macrophages are key type of antigen-presenting cells that arbitrate the first line of defense against various intracellular pathogens. Tuberculosis, both pulmonary and extrapulmonary, is an infectious disease of global concern caused by Mycobacterium tuberculosis. The bacillus is a highly successful pathogen and has acquired various strategies to downregulate critical innate-effector immune responses of macrophages, such as phagosome-lysosome fusion, autophagy, induction of cytokines, generation of reactive oxygen and nitrogen species and antigen presentation. In addition, the bacilli also subvert acquired immunity. In this review, we aim to provide an overview of different antimycobacterial immune functions of macrophage and the strategies adopted by the bacilli to manipulate these functions to favor its survival and replication inside the host.

The PPE2 protein of Mycobacterium tuberculosis translocates to host nucleus and inhibits nitric oxide production

“…NO produced by the activated macrophages plays an important role as a cytotoxic effector molecule against various pathogens including mycobacteria at least in mice model of infection115, though its role in human infection is highly debatable16. To understand a direct role of NO in the survival of M. smegmatis , we next pre-treated the C57BL6 peritoneal macrophages with either sodium nitropruside (SNP), a known NO donor (or aminoguanidine (AG), an inhibitor of nitric oxide synthase2627 before infection with Msmeg-PPE2 or Msmeg-ΔNLS-PPE2 or Msmeg-pVV16 and intracellular survival of these strains were examined.…”

“…However, the mechanisms are not well understood. Though the bacterium lacks classical virulence factors such as toxins, typical to several other bacterial pathogens, it employs vast array of factors to modulate multiple host cellular processes to favor its intracellular survival1. The ability to modulate host cellular processes through functional mimicry is a powerful tool, usually achieved through homologous enzymes that have been subverted for the benefit of pathogen and often have considerable similarities with the cognate host proteins at the primary amino acid sequence levels particularly around their active or regulatory sites3637.…”

“…Mycobacterium tuberculosis is a successful intracellular pathogen that has developed several adaptive skills and evasion mechanisms to hijack host defense processes1. Complete genomic sequencing of M. tuberculosis H37Rv genome revealed the presence of two novel gene families that comprise almost 10% of the coding capacity of the genome23.…”

“…NO can deaminate as well as directly damage bacterial DNA by generating abasic sites and strand breaks15. Though, the role of NO in human infection is debatable, several lines of evidences suggest that NO plays a contributory role in human host defense against tuberculosis116. At low pH, NO bactericidal effects are shown to be boosted16.…”

Alveolar macrophage chromatin is modified to orchestrate host response toMycobacterium bovisinfection

“…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 (Awuh and Flo, 2017; Cambier et al, 2014; de Chastellier, 2009; Schorey and Schlesinger, 2016). 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 severe immunopathology and shedding of the pathogen from the host (BoseDasgupta and Pieters, 2018; Chaurasiya, 2018; Ehrt and Schnappinger, 2009; Hussain Bhat and Mukhopadhyay, 2015; Queval et al, 2017; Stutz et al, 2018).…”