Macrophages in Tuberculosis
Tuberculosis (TB)
TB is a chronic inflammatory disease caused by a Mycobacterium tuberculosis (Mtb) infection. TB typically is a disease of the lung, which serves both as a port of entry and as the major site of disease outbreaks. This is followed by an early inflammatory response, induced by both bacterial and host factors, which results in the recruitment of leukocytes from neighboring blood vessels to the site of infection. Subversion of the death modality of macrophages, the principal host cells infected by TB, is a common feature of several other intracellular pathogens. Various bacteria and intracellular parasites induce apoptosis or necrosis following infection. While antimycobacterial therapy exists, currently available drugs are only partially effective because of the impermeable nature of the mycobacterial cell wall and the propensity of Mtb to develop resistance. One additional problem is that Mtb has the capacity to remain viable within infected hosts for a prolonged time.
Role of Macrophages in TB
Infection of a host with Mtb is initiated following the inhalation of droplets (aerosols) containing a small number of bacilli. In the early stage of Mtb infection, macrophages show pro-inflammatory responses like M1 macrophages contributing to the restriction of Mtb survival (Mtb-infected M1 macrophages are transformed into M2 macrophages with suppressive activities in their antibacterial responses over time). Alveolar macrophages can effectively phagocytize and transfer the phagocytosed Mtb to the destructive environment of lysosomes. However, some bacilli can escape from the lysosome and survive within the macrophage. These macrophages harbor the pathogen and transport it to draining lymph nodes. A small granulomatous lesion develops containing the bacteria. Mtb-infected macrophages can differentiate into foamy macrophages by the accumulation of lipid, which are hallmarks of TB lesions. When foamy macrophages leave the original granuloma to promote the dissemination, giving the bacteria access to nearby airways and thus the ability to spread within the lung and elsewhere within the body. Thus, Mtb-infected alveolar. In the case of immunodeficiency, for example, when T cell function is compromised, unrestricted growth and necrosis within macrophages cause dissemination of tubercle bacilli.
Fig.1 Generation of Mtb-infected foamy macrophages during the formation of TB granulomas. (Shim, 2020)
Strategies to Conquer Macrophages
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Interference with phagosome maturation. Mtb is internalized within alveolar macrophages. Blockade of phagosomal acidification and inhibiting the phagolysosome biogenesis can interfere with phagosome functions to promote the intracellular survival of pathogens.
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Getting access to the cytosol. Cytosolic contact of Mtb seems to be fundamental in mycobacterial host-pathogen interaction. Bacteria then progressively access the cytosol through the action of the early secretory antigen target (ESAT6) secretion system-1 (ESX-1) and dimycocerosates (DIM).
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The control of host cell death. Macrophages infected with Mtb commonly express two types of cell death, necrosis, and apoptosis. Virulent strains of Mtb may selectively induce the production of interleukin 10 (IL-10), leading to reducing tumor necrosis factor (TNFα) activity and decreasing the apoptosis of infected cells. In addition, intracellular Mtb selectively modulates autophagy to survive within the macrophages, preventing infected macrophages from undergoing apoptosis.
Therapies Targeting macrophages in TB
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Reprogramming macrophages. The Mtb-induced transformation processes from M1 to M2 macrophages are potential immunological targets of TB. Reprogramming macrophages from M2 toward M1 seem to be an approach to inhibit Mtb.
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Upregulation of the production of antimicrobial peptides in Mtb infected macrophages by phenylbutyrate and Vitamin D. Vitamin D inhibits the proliferation of Mtb inside the macrophages through stimulation of the innate immune responses during the infection.
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Targeting Mtb-infected foamy macrophages. A recent study indicated that Mtb-infected foamy macrophages could uptake more fluoroquinolones compared to non-foamy macrophages in vivo, suggesting that it is important to consider the functions of foamy macrophages for anti-TB drug treatment.
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Activation of autophagy in Mtb infected macrophages by rapamycin, metformin, or statin. Activated macrophages are capable to kill Mtb, involving autophagy. For example, rapamycin inhibits mTOR kinase activity, which in turn activates autophagy.
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Increasing anti-inflammatory responses and suppressing pro-inflammatory responses can reduce inflammation and tissue damage. Pro-inflammatory cytokines such as interferon γ (IFNγ), IL-1b, and TNF-a are known to activate autophagy, whereas anti-inflammatory cytokines IL-4, IL-10, and IL-13 seem to inhibit autophagy.
Fig.2 Host-directed therapy (HDT) against Mycobacterium tuberculosis. (Ahmed, 2020)
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References
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Shim, D.; et al. Mycobacterium tuberculosis infection-driven foamy macrophages and their implications in tuberculosis control as targets for host-directed therapy. Front Immunol. 2020, 11: 910.
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Ahmed, S.; et al. Host-directed therapy as a novel treatment strategy to overcome tuberculosis: targeting immune modulation. Antibiotics (Basel). 2020, 9(1):21-.
