Mycobacterial MCE proteins as transporters that control lipid homeostasis of the cell wall

Klepp, Laura I.; Garcia, Julia Sabio y; Forrellad, Marina Andrea; FabianaBigi,

doi:10.1016/j.tube.2021.102162

Cited by 19 publications

(15 citation statements)

References 77 publications

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“…There are four mce operons in M. tuberculosis (mce1-4), and each is composed of two yrbeAB and six mceA-F genes. These operons are present in pathogenic and non-pathogenic mycobacteria and have similarities with ATPbinding cassette transporters, where the Mce proteins serve as substrate-binding proteins and the YrbE proteins as permeases (72). Mce proteins participate in nutrient uptake, cholesterol uptake and catabolism (23,73,74), lipid homeostasis following stress responses (72) and in cell wall modification (75).…”

Section: Virulence Factorsmentioning

confidence: 99%

“…These operons are present in pathogenic and non-pathogenic mycobacteria and have similarities with ATPbinding cassette transporters, where the Mce proteins serve as substrate-binding proteins and the YrbE proteins as permeases (72). Mce proteins participate in nutrient uptake, cholesterol uptake and catabolism (23,73,74), lipid homeostasis following stress responses (72) and in cell wall modification (75). Our RNAseq data revealed that: 1) the mce1 operon was highly repressed in hypoxic and stationary phase conditions; 2) the mce2 operon was induced in hypoxia and moderately in stationary phase condition; 3) the mce3 operon was only induced in hypoxia; and 4) the mce4 operon was the least impacted showing moderate downregulation in stationary phase and in nutrient starvation (Figure 6).…”

Section: Virulence Factorsmentioning

confidence: 99%

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Commonalities of Mycobacterium tuberculosis Transcriptomes in Response to Defined Persisting Macrophage Stresses

Vilchèze

Yan²,

Casey³

et al. 2022

Front. Immunol.

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As the goal of a bacterium is to become bacteria, evolution has imposed continued selections for gene expression. The intracellular pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis, has adopted a fine-tuned response to survive its host’s methods to aggressively eradicate invaders. The development of microarrays and later RNA sequencing has led to a better understanding of biological processes controlling the relationship between host and pathogens. In this study, RNA-seq was performed to detail the transcriptomes of M. tuberculosis grown in various conditions related to stresses endured by M. tuberculosis during host infection and to delineate a general stress response incurring during persisting macrophage stresses. M. tuberculosis was subjected to long-term growth, nutrient starvation, hypoxic and acidic environments. The commonalities between these stresses point to M. tuberculosis maneuvering to exploit propionate metabolism for lipid synthesis or to withstand propionate toxicity whilst in the intracellular environment. While nearly all stresses led to a general shutdown of most biological processes, up-regulation of pathways involved in the synthesis of amino acids, cofactors, and lipids were observed only in hypoxic M. tuberculosis. This data reveals genes and gene cohorts that are specifically or exclusively induced during all of these persisting stresses. Such knowledge could be used to design novel drug targets or to define possible M. tuberculosis vulnerabilities for vaccine development. Furthermore, the disruption of specific functions from this gene set will enhance our understanding of the evolutionary forces that have caused the tubercle bacillus to be a highly successful pathogen.

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Section: Virulence Factorsmentioning

confidence: 99%

Section: Virulence Factorsmentioning

confidence: 99%

Commonalities of Mycobacterium tuberculosis Transcriptomes in Response to Defined Persisting Macrophage Stresses

Vilchèze

Yan²,

Casey³

et al. 2022

Front. Immunol.

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“…The functions of corresponding proteins have not been fully elucidated, but it is known that they belong to the transport systems necessary for interaction of mycobacteria with host cells [ 40 ]. It was shown recently that the Mce1 and Mce4 operons encode systems of lipid transportation across the cell wall [ 41 ]. Diacyltrehaloses (DAT), polyacyltrehaloses (PAT) and phthiocerol dimycocerosates (PDIM) production depend upon Mce1 operon expression.…”

Section: Resultsmentioning

confidence: 99%

An In Vivo Model of Separate M. tuberculosis Phagocytosis by Neutrophils and Macrophages: Gene Expression Profiles in the Parasite and Disease Development in the Mouse Host

Kondratieva

Majorov

Grigorov

et al. 2022

IJMS

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The role of neutrophils in tuberculosis infection remains less well studied compared to that of the CD4+ T-lymphocytes and macrophages. Thus, alterations in Mycobacterium tuberculosis transcription profile following phagocytosis by neutrophils and how these shifts differ from those caused by macrophage phagocytosis remain unknown. We developed a mouse model that allows obtaining large amounts of either neutrophils or macrophages infected in vivo with M. tuberculosis for mycobacteria isolation in quantities sufficient for the whole genome RNA sequencing and aerosol challenge of mice. Here, we present: (i) the differences in transcription profiles of mycobacteria isolated from liquid cultures, neutrophils and macrophages infected in vivo; (ii) phenotypes of infection and lung inflammation (life span, colony forming units (CFU) counts in organs, lung pathology, immune cells infiltration and cytokine production) in genetically TB-susceptible mice identically infected via respiratory tract with neutrophil-passaged (NP), macrophage-passaged (MP) and conventionally prepared (CP) mycobacteria. Two-hour residence within neutrophils caused transcriptome shifts consistent with mycobacterial transition to dormancy and diminished their capacity to attract immune cells to infected lung tissue. Mycobacterial multiplication in organs did not depend upon pre-phagocytosis, whilst survival time of infected mice was shorter in the group infected with NP bacilli. We also discuss possible reasons for these phenotypic divergences.

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“…Regarding the SNPs in potential virulence factors, mce genes have been traditionally related to cell entry ( Arruda et al., 1993 ). For the mce3 operon, this function was demonstrated for the mce3C gene ( Zhang et al., 2018 ); however, the complete mce3 operon seems more related to lipid transport ( Klepp et al., 2022 ). The MtZ strain has two SNPs in this operon, one of them a frameshift, suggesting a possible defect in this lipid transport.…”

Section: Discussionmentioning

confidence: 99%

“…The MtZ strain has two SNPs in this operon, one of them a frameshift, suggesting a possible defect in this lipid transport. Nevertheless, it has been shown that the different mce operons can interact with each other ( Klepp et al., 2022 ); therefore, complementation between systems could be possible. In addition, the entire mce3 operon is absent from M. bovis and most other animal-adapted strains of the M. tuberculosis complex , suggesting that it is not required for infecting the macrophages and preventing that the frameshift SNP attenuates the MtZ strain.…”

Section: Discussionmentioning

confidence: 99%

The MtZ Strain: Molecular Characteristics and Outbreak Investigation of the Most Successful Mycobacterium tuberculosis Strain in Aragon Using Whole-Genome Sequencing

Comín

Madacki

Rabanaque

et al. 2022

Front. Cell. Infect. Microbiol.

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Since 2004, a tuberculosis surveillance protocol has been carried out in Aragon, thereby managing to detect all tuberculosis outbreaks that take place in the community. The largest outbreak was caused by a strain named Mycobacterium tuberculosis Zaragoza (MtZ), causing 242 cases as of 2020. The main objective of this work was to analyze this outbreak and the molecular characteristics of this successful strain that could be related to its greater transmission. To do this, we first applied whole-genome sequencing to 57 of the isolates. This revealed two principal transmission clusters and six subclusters arising from them. The MtZ strain belongs to L4.8 and had eight specific single nucleotide polymorphisms (SNPs) in genes considered to be virulence factors [ptpA, mc3D, mc3F, VapB41, pks15 (two SNPs), virS, and VapC50]. Second, a transcriptomic study was carried out to better understand the multiple IS6110 copies present in its genome. This allowed us to observe three effects of IS6110: the disruption of the gene in which the IS6110 is inserted (desA3), the overexpression of a gene (ppe38), and the absence of transcription of genes (cut1:Rv1765c) due to the recombination of two IS6110 copies. Finally, because of the disruption of ppe38 and ppe71 genes by an IS6110, a study of PE_PGRS secretion was carried out, showing that MtZ secretes these factors in higher amounts than the reference strain, thereby differing from the hypervirulent phenotype described for the Beijing strains. In conclusion, MtZ consists of several SNPs in genes related to virulence, pathogenesis, and survival, as well as other genomic polymorphisms, which may be implicated in its success among our population.

show abstract

Mycobacterial MCE proteins as transporters that control lipid homeostasis of the cell wall

Cited by 19 publications

References 77 publications

Commonalities of Mycobacterium tuberculosis Transcriptomes in Response to Defined Persisting Macrophage Stresses

Commonalities of Mycobacterium tuberculosis Transcriptomes in Response to Defined Persisting Macrophage Stresses

An In Vivo Model of Separate M. tuberculosis Phagocytosis by Neutrophils and Macrophages: Gene Expression Profiles in the Parasite and Disease Development in the Mouse Host

The MtZ Strain: Molecular Characteristics and Outbreak Investigation of the Most Successful Mycobacterium tuberculosis Strain in Aragon Using Whole-Genome Sequencing

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