Macrophage: A Cell With Many Faces and Functions in Tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) is the causative agent of human tuberculosis (TB) which primarily infects the macrophages. Nearly a quarter of the world’s population is infected latently by Mtb. Only around 5%–10% of those infected develop active TB disease, particularly during suppressed host immune conditions or comorbidity such as HIV, hinting toward the heterogeneity of Mtb infection. The aerosolized Mtb first reaches the lungs, and the resident alveolar macrophages (AMs) are among the first cells to encounter the Mtb infection. Evidence suggests that early clearance of Mtb infection is associated with robust innate immune responses in resident macrophages. In addition to lung-resident macrophage subsets, the recruited monocytes and monocyte-derived macrophages (MDMs) have been suggested to have a protective role during Mtb infection. Mtb, by virtue of its unique cell surface lipids and secreted protein effectors, can evade killing by the innate immune cells and preferentially establish a niche within the AMs. Continuous efforts to delineate the determinants of host defense mechanisms have brought to the center stage the crucial role of macrophage phenotypical variations for functional adaptations in TB. The morphological and functional heterogeneity and plasticity of the macrophages aid in confining the dissemination of Mtb. However, during a suppressed or hyperactivated immune state, the Mtb virulence factors can affect macrophage homeostasis which may skew to favor pathogen growth, causing active TB. This mini-review is aimed at summarizing the interplay of Mtb pathomechanisms in the macrophages and the implications of macrophage heterogeneity and plasticity during Mtb infection.

Reinventing the human tuberculosis (TB) granuloma: Learning from the cancer field

“…Anti-inflammatory M2 macrophages support angiogenesis and extracellular matrix remodeling and are involved in suppression of Th1 and CTL responses ( 31 ). Alveolar macrophages are the main host cell to become infected with Mtb in the early stage of infection ( 32 ) and bacteria are likely allowed to replicate in these cells because of their inherent anti-inflammatory or tolerant function in lung homeostasis ( 33 ). Polarization of anti-inflammatory or immunoregulatory macrophages may be considered an immune evasion mechanism used by virulent strains of Mtb to promote long-term persistence in the GME ( 34 – 37 ).…”

“…It is worth noticing the emerging data uncover the M1/M2 classification as an oversimplification of macrophage polarization. The complexity of monocytes/macrophages in the tissue microenvironment in vivo show a poor correlation with the M1/M2 designation, which suggest that distinct populations play specific roles in Mtb infection or tumor progression ( 33 , 43 – 45 ).…”

“…Modern single-cell sequencing and tracer technologies have enabled identification of diverse subsets of macrophages in tissues such as the lung with relevance for different disease conditions ( 33 , 43 ). These include tissue-resident and monocyte-derived alveolar macrophages as well as interstitial macrophages in Mtb-infected lungs ( 46 , 47 ) and several functionally distinct monocyte/macrophage populations that predicted the prognosis of lung adenocarcinoma ( 48 ).…”

Immunoregulation via Cell Density and Quorum Sensing-like Mechanisms: An Underexplored Emerging Field with Potential Translational Implications

“…Macrophages undergo multifaceted regulation during the course of infectious diseases. In the lung microenvironment, alveolar macrophages are sentinel cells responsible for maintaining lung homeostasis, clearing cellular debris, and protecting against pathogen invasion [ 165 , 166 ]. However, pathogens have evolved exquisite mechanisms to evade immune surveillance, survive in hostile microenvironments, and subvert host responses.…”

Mycobacterium tuberculosis protein MoxR1 enhances virulence by inhibiting host cell death pathways and disrupting cellular bioenergetics

“…This extraordinary ability gained by M. tb is attributed to the evolution of protein moonlighting functions to compensate for reductive evolution [ 1–3 ]. Professional phagocytes such as macrophages, neutrophils, and dendritic cells serve as the primary defence arsenal against M. tb [ 4 ]. These phagocytes possess diverse pattern recognition receptors (PRRs), including toll-like receptors (TLRs) that are highly conserved, which enable them to recognize and start innate immunological reactions in response to different M. tb antigens [ 5–7 ].…”