A<i>Mycobacterium tuberculosis</i>effector targets mitochondrion, controls energy metabolism and limits cytochrome c exit

Martin, Marianne; DeVisch, Angelique; Boudehen, Yves-Marie; Barthe, Philippe; Gutierrez, Claude; Turapov, Obolbek; Aydogan, Talip; Heriaud, Laurène; Gracy, Jérôme; Mukamolova, Galina V.; Letourneur, François; Cohen‐Gonsaud, Martin

doi:10.1101/2021.01.31.428746

Cited by 4 publications

(2 citation statements)

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“…The Rv1269c gene encodes a secreted protein with an unknown function. It was shown that Rv1269c product may damage the host’s mitochondria [ 33 ]. Based on a proteomic approach, the study [ 34 ] claimed that Rv1269c is more efficiently secreted in modern Beijing isolates because it was significantly more abundant in cell lysates of ancient Beijing isolates, whereas the transcriptional levels were similar for modern and ancient Beijing MTB.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Study of Drug Resistant Mycobacterium tuberculosis and Its Intra-Host Evolution during Treatment

et al. 2022

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The emergence of drug resistant Mycobacterium tuberculosis (MTB) strains has become a global public health problem, while, at the same time, there has been development of new antimicrobial agents. The main goals of this study were to determine new variants associated with drug resistance in MTB and to observe which polymorphisms emerge in MTB genomes after anti-tuberculosis treatment. We performed whole-genome sequencing of 152 MTB isolates including 70 isolates as 32 series of pre- and post-treatment MTB. Based on genotypes and phenotypic drug susceptibility, we conducted phylogenetic convergence-based genome-wide association study (GWAS) with streptomycin-, isoniazid-, rifampicin-, ethambutol-, fluoroquinolones-, and aminoglycosides-resistant MTB against susceptible ones. GWAS revealed statistically significant associations of SNPs within Rv2820c, cyp123 and indels in Rv1269c, Rv1907c, Rv1883c, Rv2407, Rv3785 genes with resistant MTB phenotypes. Comparisons of serial isolates showed that treatment induced different patterns of intra-host evolution. We found indels within Rv1435c and ppsA that were not lineage-specific. In addition, Beijing-specific polymorphisms within Rv0036c, Rv0678, Rv3433c, and dop genes were detected in post-treatment isolates. The appearance of Rv3785 frameshift insertion in 2 post-treatment strains compared to pre-treatment was also observed. We propose that the insertion within Rv3785, which was a GWAS hit, might affect cell wall biosynthesis and probably mediates a compensatory mechanism in response to treatment. These results may shed light on the mechanisms of MTB adaptation to chemotherapy and drug resistance formation.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Study of Drug Resistant Mycobacterium tuberculosis and Its Intra-Host Evolution during Treatment

et al. 2022

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“…Upon expression in eukaryotic cells, it is transported to the intermembrane space of mitochondria, thereby boosting ATP production through the enhancement of the oxidative phosphorylation metabolic pathway. This, in turn, influences the metabolic and apoptotic responses in macrophages infected with Mtb ( Martin et al., 2023 ). As a conserved latency antigen, Rv1813c represents a promising candidate for vaccine development.…”

Section: Antigen Selection For Tb Vaccinesmentioning

confidence: 99%

Optimizing antigen selection for the development of tuberculosis vaccines

Yang,

Chen,

Xia

2024

Cell Insight

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C-terminal region of Rv1039c (PPE15) protein of Mycobacterium tuberculosis targets host mitochondria to induce macrophage apoptosis

Priyanka,

Sharma,

Varma-Basil

et al. 2024

Apoptosis

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The genome of Mycobacterium tuberculosis (Mtb) encodes a unique family called Proline-Glutamate/Proline-Proline-Glutamate (PE/PPE) gene family, which is exclusive to pathogenic mycobacterium. Several proteins of this family are known to be virulent and utilize host signalling and cell death pathways leading to host immune response modulation, but functions of many of the PE/PPE proteins are yet to be identi ed. We studied the Rv1039c (PPE15) protein, which is known to be expressed at later stages of infection and known to be upregulated during dormancy. The C-terminal region of Rv1039c was found to be disordered, coiled and hydrophobic in nature and was observed to target the mitochondria of THP1 macrophages. Rv1039c with a deleted C-terminal reduced the mitochondrial perturbations, resulting in reduced depolarization of the mitochondrial membrane and the generation of mitochondrial superoxides. The C-terminal region of Rv1039c is responsible for activation of caspases 3, 7 and 9 along with enhanced expression of pro-apoptotic factors like Bax and Bim. Rv1039c also induced Cytochrome-C release from the mitochondria. Additionally, the C-terminal region of Rv1039c was observed to upregulate the expression levels of TLR4-NF-κB-TNF-α and antigen presenting HLA-DR molecules. These ndings revealed that the C-terminal region of Rv1039c is a molecular mimic of a proapoptotic host protein, inducing mitochondria-dependent macrophage apoptosis.

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AMycobacterium tuberculosiseffector targets mitochondrion, controls energy metabolism and limits cytochrome c exit

Cited by 4 publications

References 61 publications

Genome-Wide Study of Drug Resistant Mycobacterium tuberculosis and Its Intra-Host Evolution during Treatment

Genome-Wide Study of Drug Resistant Mycobacterium tuberculosis and Its Intra-Host Evolution during Treatment

Optimizing antigen selection for the development of tuberculosis vaccines

C-terminal region of Rv1039c (PPE15) protein of Mycobacterium tuberculosis targets host mitochondria to induce macrophage apoptosis

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