MITOCHONDRIA AND ANTIAPOPTOTIC PROTEIN BCL-2 IN MYCOBACTERIUM-HOST CELL RELATIONSHIPS IN GRANULOMAS OF MICE WITH LATENT TUBERCULOUS INFECTION

Original title

РОЛЬ МИТОХОНДРИЙ И АНТИАПОПТОЗНОГО БЕЛКА BCL-2 ВО ВЗАИМООТНОШЕНИЯХ МИКОБАКТЕРИЙ С КЛЕТКАМИ-ХОЗЯЕВАМИ В ГРАНУЛЕМАХ МЫШЕЙ С ЛАТЕНТНОЙ ТУБЕРКУЛЕЗНОЙ ИНФЕКЦИЕЙ

Authors

Elena Ufimtseva

Contact information

Research Institute of Biochemistry, Federal Research Center of Fundamental and Translation Medicine, Novosibirsk, Этот адрес электронной почты защищён от спам-ботов. У вас должен быть включен JavaScript для просмотра.

Pages

139-141

DOI

10.31255/978-5-94797-318-1-139-141

Abstract

Tuberculosis (TB) is a leading worldwide health problem. Macrophages and dendritic cells are host cells for pathogenic mycobacteria, which can invade these cells and persist in them for years or even for decades. The latent, symptom-free stage of TB infection is characterized by the formation of granulomas, specific aggregates of immune cells containing mycobacteria. Several potential mechanisms by which mycobacteria can survive in granuloma cells and defy the immune system of the host organism are proposed. Mycobacteria prevent the phagosomes containing them from merging with host cells’ lysosomes and cannot thus be destroyed by lysosomal enzymes. Also, mycobacteria can modulate the expression of proinflammatory and antiinflammatory cytokines involved in the formation of cellular responses and a specific immune response of the host organism to infection. Mycobacteria cause infected cells to die either by apoptosis or by necrosis. The apoptotic death of macrophages containing mycobacteria is considered the main mechanism by which animals and human organisms oppose TB infection and control its development. We have compared Mycobacterium-host cell relationships in individual granuloma cells from mice with latent TB infection and cells from mouse bone marrow and peritoneal cultures infected with BCG vaccine (attenuated live strain of M. bovis, the Bacillus Calmette-Guérin) in vitro and shown that increased death rates were revealed for macrophages heavily loaded with mycobacteria after acute BCG infection in vitro, while in ex vivo cultures granuloma macrophages with large numbers of BCG mycobacteria in them were still viable and had neither apoptotic nor necrotic morphology.

Since different specific cellular responses to latent chronic and acute BCG infection in mouse cells were determined, we analyzed granulomas isolated from the lungs, spleens and bone marrow of Balb/c mice with latent BCG infection for the presence of inducers and markers of apoptotic cell death. In granuloma cells with increased levels of the inducer of apoptosis TNFα, proapoptotic proteins Вах and Ваd, death receptor Fas/CD95 and scavenge receptor CD36, we did not observe P53 stabilization or caspase-3 activation in the cytoplasm or nuclei of macrophages and dendritic cells, irrespective of the presence or absence of acid-fast BCG mycobacteria in them. The survival receptor CD30 was detected on the cell membranes of only few granuloma macrophages. However, at later times of latent TB infection in mice, virtually all macrophages and other granuloma cell types had considerable amounts of the antiapoptotic protein Bcl-2 in the cytoplasm and, probably, mitochondria, in contrast to macrophages from bone barrow cell cultures and peritoneal exudates infected with BCG vaccine in vitro. Preservation of mitochondrial ΔΨm during staining of living granuloma macrophages containing large amounts of the Bcl-2 protein was indicative of its involvement in maintaining the integrity of mitochondrial elements and the protection of granuloma cells from death, because in similar experiments the control macrophages that did not have any Bcl-2 protein in them had considerably reduced ΔΨm and exhibited morphological signs of apoptotic death.

Taken together, our results suggest that the antiapoptotic protein Bcl-2 has been proposed to contribute to the viability of granulomas macrophages not only in ex vivo culture, but also in the animal organism when faced with mycobacterial, proinflammatory and proapoptotic factors operating in granulomatous inflammatory lesions at various times of latent TB infection in mice.