Molecular basis of mycobacterial survival in macrophages

Abstract

Macrophages play an essential role in the immune system by ingesting and degrading invading pathogens, initiating an inflammatory response and instructing adaptive immune cells, and resolving inflammation to restore homeostasis. More interesting is the fact that some bacteria have evolved to use macrophages as a natural habitat and tools of spread in the host, e.g., Mycobacterium tuberculosis (Mtb) and some non-tuberculous mycobacteria (NTM). Mtb is considered one of humanity's most successful pathogens and is the causal agent of tuberculosis, while NTMs cause opportunistic infections all of which are of significant public health concern. Here, we describe mechanisms by which intracellular pathogens, with an emphasis on mycobacteria, manipulate macrophage functions to circumvent killing and live inside these cells even under considerable immunological pressure. Such macrophage functions include the selective evasion or engagement of pattern recognition receptors, production of cytokines, reactive oxygen and nitrogen species, phagosome maturation, as well as other killing mechanisms like autophagy and cell death. A clear understanding of host responses elicited by a specific pathogen and strategies employed by the microbe to evade or exploit these is of significant importance for the development of effective vaccines and targeted immunotherapy against persistent intracellular infections like tuberculosis.

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

“…It is thereby rendering the intraphagosomal environment more compatible with bacterial survival and replication. [122][123][124] miR-30A, an autophagy-related microRNA, acts as a negative regulator of autophagy in MTB infected macrophages and that H37Rv triggered an increase in miR-30A levels may play an important role in mediating the escape of MTB from killing by macrophages due to inhibited autophagic pathways. 125 DRAM2 (DNA damage-regulated autophagy modulator 2) is a crucial coordinator of autophagy activation that enhances antimicrobial activity against MTB.…”

“…Survival mechanisms of MTB are the inhibition of phagosomes acidification and maturation. It is thereby rendering the intraphagosomal environment more compatible with bacterial survival and replication …”

HMGN2 regulates non‐tuberculous mycobacteria survival via modulation of M1 macrophage polarization

“…non-tuberculous mycobacteria replication. 9 In general, to fight against non-tuberculous mycobacteria infection, macrophage can initiate innate immunity though recognition of pathogen-associated molecular patterns (PAMP) by pattern-recognition receptors (PRRs), 10 such as activation of phagocytic pathway, production of nitric oxide (NO) and antibacterial peptide, [11][12][13][14] release of pro-inflammatory cytokines and chemokines, 12,15,16 which was conceptually introduced as classical activation of macrophage, also termed as M1 polarization. 17 Following the acute inflammatory burst, however, macrophages can remove cell debris and apoptotic inflammatory cells by so-called efferocytosis and polarize into alternatively activated, M2 macrophages.…”

Genetic variation/evolution and differential host responses resulting from in-patient adaptation ofMycobacterium avium

“…Other factors such as tumor necrosis factor alpha (TNFα) produced by activated macrophages and T cells, are not only important in enhancing the microbicidal capacity but also in inducing the adaptive response, in synergy with IFNγ (12, 13). Pro-inflammatory cytokines like IL-6 and IL-1β have also been shown to play a role in mycobacterial infections (11, 14–17). IL-1β along with IL-6 and TNFα have been observed to be suppressed by the most virulent strains of Mav (18).…”