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Lysosome repositioning as an autophagy escape mechanism by Mycobacterium tuberculosis Beijing strain.

ABSTRACT: Induction of host cell autophagy by starvation was shown to enhance lysosomal delivery to mycobacterial phagosomes, resulting in the restriction of Mycobacterium tuberculosis reference strain H37Rv. Our previous study showed that strains belonging to M. tuberculosis Beijing genotype resisted starvation-induced autophagic elimination but the factors involved remained unclear. Here, we conducted RNA-Seq of macrophages infected with the autophagy-resistant Beijing strain (BJN) compared to macrophages infected with H37Rv upon autophagy induction by starvation. Results identified several genes uniquely upregulated in BJN-infected macrophages but not in H37Rv-infected cells, including those encoding Kxd1 and Plekhm2, which function in lysosome positioning towards the cell periphery. Unlike H37Rv, BJN suppressed enhanced lysosome positioning towards the perinuclear region and lysosomal delivery to its phagosome upon autophagy induction by starvation, while depletion of Kxd1 and Plekhm2 reverted such effects, resulting in restriction of BJN intracellular survival upon autophagy induction by starvation. Taken together, these data indicated that Kxd1 and Plekhm2 are important for the BJN strain to suppress lysosome positioning towards the perinuclear region and lysosomal delivery into its phagosome during autophagy induction by starvation to evade starvation-induced autophagic restriction.

SUBMITTER: Laopanupong T

PROVIDER: S-EPMC7900199 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Lysosome repositioning as an autophagy escape mechanism by Mycobacterium tuberuculosis Beijing strain

Project description:Autophagy is a conserved lysosomal-dependent cellular degradation process shown to play a key role in immune defense against Mycobacterium tuberculosis inside host macrophages. Induction of autophagy enhances mycobacterial phagosome acquisition of lysosomal hydrolases, resulting in the destruction of intracellular M. tuberculosis reference strain H37Rv and strains belonging to the East African Indian genotype. However, our previous study showed that strains belonging to the hypervirulent M. tuberculosis Beijing genotype have a special ability to resist autophagic killing but the mechanism involved remains unclear. In this study, we carried out whole transcriptome analyses of host macrophages infected with the autophagy resistant Beijing strain compared to that of H37Rv. Our results identified several genes that are differentially regulated in the Beijing strain-infected host cells including those function in the lysosome positioning pathway. Host macrophages depleted of Kxd1 and Pleckhm2, two proteins in this pathway, can now enhance the lysosomal hydrolase acquisition into the Beijing phagosomes and restrict the bacterial survival upon autophagy induction. High-content image analysis showed an increase in lysosome numbers at the cell periphery in host cells infected with the autophagy resistant Beijing strain in a Pleckhm2-dependent manner. Taken together, these data indicated that the M. tuberculosis Beijing strain escapes autophagic elimination by upregulating the lysosome positioning pathway resulting in an increase in lysosome relocation toward the cell periphery and therefore sparing the mycobacteria from autophagic restriction. Our work thus identified new strategy employed by M. tuberculosis to evade autophagy which may provide potential new targets for drug discovery against tuberculosis

2021-03-02 | GSE151633 | GEO

Lysosome repositioning as an autophagy escape mechanism by Mycobacterium tuberuculosis Beijing strain

Project description:Lysosome repositioning as an autophagy escape mechanism by Mycobacterium tuberuculosis Beijing strain

| PRJNA636677 | ENA

The autophagy-resistant Mycobacterium tuberculosis Beijing strain upregulates KatG to evade starvation-induced autophagic restriction.

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| S-EPMC8829027 | biostudies-literature

Protection by novel vaccine candidates, Mycobacterium tuberculosis ΔmosR and ΔechA7, against challenge with a Mycobacterium tuberculosis Beijing strain.

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Differential MicroRNA Expression in Human Macrophages with Mycobacterium tuberculosis Infection of Beijing/W and Non-Beijing/W Strain Types.

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| S-EPMC4460131 | biostudies-literature

Transcriptional profile of Beijing/East-Asian Mycobacterium tuberculosis isolates

Project description:Transcriptional profile comparison among Beijing and non-Beijing M. tuberculosis isolates.

2016-06-24 | GSE83677 | GEO

Pyrosequencing identification of Mycobacterium tuberculosis W-Beijing.

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| S-EPMC2799434 | biostudies-literature

Outbreak of <i>Mycobacterium tuberculosis</i> Beijing Strain in a High School in Yunnan, China.

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| S-EPMC7124909 | biostudies-literature

Diagnostic Potential of a PPE Protein Derived from <i>Mycobacterium tuberculosis</i> Beijing/K Strain.

Project description:PurposeThe prevalence of Mycobacterium tuberculosis (M. tb) and the status of M. bovis BCG vaccination may affect host immune responses to M. tb antigens. Understanding of the predominant local M. tb strain and immune signatures induced by its strain-specific antigens may contribute to an improved diagnosis of tuberculosis (TB). The aim of this study was to determine immune responses to M. tb antigen which was identified from the hyper-virulent Beijing/K strain in South Korea.Materials and methodsPulmonary TB patients (n=52) and healthy subjects (n=92) including individuals with latent TB infection (n=31) were recruited, and QuantiFERON-TB Gold In-Tube tests were performed. The Beijing/K-antigen specific immune signatures were examined by diluted whole blood assays and multiplex bead arrays in a setting where nationwide BCG vaccination is employed.ResultsStatistical analyses demonstrated that three [C-X-C motif chemokine (CXCL10), interleukin (IL)-6, interferon (IFN)-α] of 17 cytokines/chemokines distinguished active cases from healthy controls following stimulation with the Beijing/K-specific antigen. IFN-α also differentiated between active diseases and latent TB infection (p<0.01), and the detection rate of TB was dramatically increased in combination with IL-6 and CXCL10 at the highest levels of specificity (95-100%).ConclusionOur data indicate that immune signatures to the M. tb Beijing/K-specific antigen can provide useful information for improved TB diagnostics. The antigen may be developed as a diagnostic marker or a vaccine candidate, particularly in regions where the M. tb Beijing/K strain is endemic.

| S-EPMC7471075 | biostudies-literature

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