The Role of Metallic Nanoparticles in Inhibition of Mycobacterium Tuberculosis and Enhances Phagosome Maturation into the Infected Macrophage

Abstract

This review focuses on the role of gallium (Ga) nanoparticles (NPs) to enhance phagosome maturation into the Mycobacterium tuberculosis-infected macrophage and the role of magnetic iron NPs as nanocarriers of antituberculosis drugs. The literature shows that silver (Ag) and zinc oxide (ZnO) NPs with dimensions less than 10 nm can penetrate directly through the macrophage bilayer membrane. Ag NPs increase the permeability membrane by motiving the aggregation of proteins in the periplasmic space and forming nano-sized pores. ZnO NPs can interact with the membrane of M. tuberculosis, which leads to the formation of surface pores and the release of intracellular nucleotides. The colloidal Ag:ZnO mixture NPs with 1:1 ratio can eliminate M. tuberculosis and shows the lowest cytotoxicity effects on MCF-7 and THP-1 cell lines. Ag/ZnO nanocrystals are not able to kill M. tuberculosis alone ex-vivo. Hence, bimetallic gold (Au)/Ag NPs possessed high efficiency to inhibit M. tuberculosis in an ex-vivo THP-1 infection model. Co-delivery of mixed MeNPs into a polymeric carrier collaborated to selective uptake by macrophages through passive targeting, initial burst release of ions from the encapsulated metallic (Me) NPs, and eventually, reduction of MeNPs toxicity, and plays a pivotal role in increasing the antitubercular activity compared to use alone. In addition, Ga NPs can import drugs to the macrophage, inhibit M. tuberculosis growth, and reduce the inhibition of phagosome maturation. Magnetic encapsulated NPs exhibited good drug release properties and might be suitable as carriers of antituberculosis drugs.

Keywords: Macrophages; Metal Nanoparticles; Mycobacterium tuberculosis; Pharmaceutical Preparations.

Figure 1

The infection pathways of Mycobacterium tuberculosis in human macrophage cells leading to the formation of a granuloma (1-4). Resident alveolar macrophages phagocytes inhaled M. tuberculosis and products the pro-inflammatory response and recruitment of fibroblasts, lymphocytes, neutrophils, natural killer (NK) cells, collagens, necrotic tissues, dendritic cells, foamy macrophages, infected apoptotic macrophage, infected apoptotic epithelial macrophages, and epithelial macrophages, and the formation of a granuloma. However, if the human immune system for any reason is weakened, M. tuberculosis is activated and replicated within the granuloma structure. In this case, the necrotic nucleus of granuloma develops. When the number of M. tuberculosis is increased within the granuloma, it ruptures, and M. tuberculosis is spilled into the airways. Each of the bacteria has the potential to infect other alveolar macrophages to the formation of a new granuloma.

Figure 2

Survival and adaptive mechanisms of Myobacterium tuberculosis in macrophages. Some M. tuberculosis can enter into the alveolar macrophages through a non-phagocytic pathway called clathrin-independent endocytosis. M. tuberculosis can then escape from phagosomes and release into the cytosol of macrophages. M. tuberculosis can induce the expression of anti-apoptosis genes (Bcl-2) into the macrophages. The absorption of H⁺, H₂O₂, O₂, NO₂, and OH also are inhibited to control the acidification of phagosome harboring M. tuberculosis. M. tuberculosis can escape from phagolysosome by producing ESAT-6 proteins, Wiskott-Aldrich syndrome protein (WASP), and CFP-10 chaperone. M. tuberculosis prevents transforming of primary endosomes in phagolysosome via the reducing of levels of proton ATPase inside the endosomes, connecting the inducible iNOS and elimination of the phosphatidylinositol 3-phosphate (PI3P). Tryptophan-aspartate containing coat (TACO) proteins, represents a component of the phagosome coat that is released earlier than phagosome fusion with or maturation into lysosomes. In macrophages containing TACO, it leads to preventing to forming phagolysosome and following that M. tuberculosis can survive within the phagosome.

Figure 3

Colloidal ZnO nanoparticles (NPs) can penetrate the bilayer membrane directly and accumulate in lysosomes. (A) Lysosomes containing ZnO NPs are integrated into infected phagosomes and eliminate M tuberculosis; colloidal Ag NPs alone cannot kill M. tuberculosis. (B) Opposed to mixture Ag/ZnO nanocrystals. (C, D) Ag/ZnO-rifampicin is able to eliminate M. tuberculosis into the phagosome. (E) Encapsulated magnetic NPs and antibiotics loaded polymers import to macrophage by endocytosis and subsequently release NPs and antibiotics in the cytosol. Mixed magnetic NPs and antitubercular NPs are able to kill M. tuberculosis into the macrophage. (F) The macrophage infected with M. tuberculosis presented an expression of cathepsin D, which plays an important role in macrophage activation.