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New findings of Toll-like receptors involved in Mycobacterium tuberculosis infection.

ABSTRACT: Tuberculosis (TB), an important issue in the present age, affects millions of people each year. The infectious agent of TB, Mycobacterium tuberculosis (Mtb), interacts with the immune system which prevents the development of this bacterium as much as possible. In fact, the receptors on the surface of immune cells identify the bacteria, one of which is Toll-like receptors (TLRs). Different TLRs including 2, 4, 9 and 8 play critical roles in tuberculosis infection. In this paper, we focused on the role of TLRs which interact with different components of Mtb and, consequently, prevent the entrance and influence of bacteria on the body.

SUBMITTER: Faridgohar M

PROVIDER: S-EPMC5560203 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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New findings of Toll-like receptors involved in Mycobacterium tuberculosis infection.

Faridgohar Majid M Nikoueinejad Hassan H

Pathogens and global health 20170717 5

Tuberculosis (TB), an important issue in the present age, affects millions of people each year. The infectious agent of TB, Mycobacterium tuberculosis (Mtb), interacts with the immune system which prevents the development of this bacterium as much as possible. In fact, the receptors on the surface of immune cells identify the bacteria, one of which is Toll-like receptors (TLRs). Different TLRs including 2, 4, 9 and 8 play critical roles in tuberculosis infection. In this paper, we focused on the ...[more]

PMID: 28715935

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Project description:The genome of Mycobacterium tuberculosis, the causal organism of tuberculosis (TB), encodes a unique protein family known as the PE/PPE/PGRS family, present exclusively in the genus Mycobacterium and nowhere else in the living kingdom, with largely unexplored functions. We describe the functional significance of the PGRS domain of Rv0297, a member of this family. In silico analyses revealed the presence of intrinsically disordered stretches and putative endoplasmic reticulum (ER) localization signals in the PGRS domain of Rv0297 (Rv0297PGRS). The PGRS domain aids in ER localization, which was shown by infecting macrophage cells with M. tuberculosis and by overexpressing the protein by transfection in macrophage cells followed by activation of the unfolded protein response, as evident from increased expression of GRP78/GRP94 and CHOP/ATF4, leading to disruption of intracellular Ca2+ homeostasis and increased nitric oxide (NO) and reactive oxygen species (ROS) production. The consequent activation of the effector caspase-8 resulted in apoptosis of macrophages, which was Toll-like receptor 4 (TLR4) dependent. Administration of recombinant Rv0297PGRS (rRv0297PGRS) also exhibited similar effects. These results implicate a hitherto-unknown role of the PGRS domain of the PE_PGRS protein family in ER stress-mediated cell death through TLR4. Since this protein is already known to be present at later stages of infection in human granulomas it points to the possibility of it being employed by M. tuberculosis for its dissemination via an apoptotic mechanism.IMPORTANCE Apoptosis is generally thought to be a defense mechanism in protecting the host against Mycobacterium tuberculosis in early stages of infection. However, apoptosis during later stages in lung granulomas may favor the bacterium in disseminating the disease. ER stress has been found to induce apoptosis in TB granulomas, in zones where apoptotic macrophages accumulate in mice and humans. In this study, we report ER stress-mediated apoptosis of host cells by the Rv0297-encoded PE_PGRS5 protein of M. tuberculosis exceptionally present in the pathogenic Mycobacterium genus. The PGRS domain of Rv0297 aids the protein in localizing to the ER and induces the unfolded protein response followed by apoptosis of macrophages. The effect of the Rv0297PGRS domain was found to be TLR4 dependent. This study presents novel insights on the strategies employed by M. tuberculosis to disseminate the disease.

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New findings of Toll-like receptors involved in Mycobacterium tuberculosis infection.

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New findings of Toll-like receptors involved in Mycobacterium tuberculosis infection.

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