<sup>1</sup>H NMR-based Metabolomic Profiling in Mice Infected with <i>Mycobacterium tuberculosis</i>

Shin, Ji Hyun; Yang, Ji; Jeon, Bo Young; Yoon, Yoo Jeong; Cho, Sang Nae; Kang, Yeon‐Ho; Ryu, Do Hyun; Hwang, Gwi Seo

doi:10.1021/pr101054m

Cited by 210 publications

(201 citation statements)

References 54 publications

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“…This protein was shown to partially depend on the ESX-5 secretion system for export. It would be interesting to see if secreted ALD has a complementary role to play, particularly because the relative quantities of certain amino acids, such as alanine, are found to increase in granulomatous lesions (63,64). Altogether, our findings point toward an important function of the three replicate ESAT-6 regions of ESX-5 in protein secretion and virulence of mycobacteria.…”

Section: Discussionmentioning

confidence: 78%

A Duplicated ESAT-6 Region of ESX-5 Is Involved in Protein Export and Virulence of Mycobacteria

et al. 2015

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The ESX-5 secretion system of Mycobacterium tuberculosis is important for bacterial virulence and for the secretion of the large PE/PPE protein family, whose genes constitute 10% of the M. tuberculosis genome. A four-gene region of the ESX-5 system is duplicated three times in the M. tuberculosis genome, but the functions of these duplicates are unknown. Here we investigated one of these duplicates: the region carrying the esxI, esxJ, ppe15, and pe8 genes (ESX-5a). An ESX-5a deletion mutant in the model system M. marinum background was deficient in the secretion of some members of the PE/PPE family of proteins. Surprisingly, we also identified other proteins that are not members of this family, thus expanding the range of ESX-5 secretion substrates. In addition, we demonstrated that ESX-5a is important for the virulence of M. marinum in the zebrafish model. Furthermore, we showed the role of the M. tuberculosis ESX-5a region in inflammasome activation but not host cell death induction, which is different from the case for the M. tuberculosis ESX-5 system. In conclusion, the ESX-5a region is nonredundant with its ESX-5 paralog and is necessary for secretion of a specific subset of proteins in M. tuberculosis and M. marinum that are important for bacterial virulence of M. marinum. Our findings point to a role for the three ESX-5 duplicate regions in the selection of substrates for secretion via ESX-5, and hence, they provide the basis for a refined model of the molecular mechanism of this type VII secretion system. Mycobacterium tuberculosis is an extremely successful pathogen that employs various strategies to evade immune responses and persist within the host (1, 2). Integral to this manipulation of the host by M. tuberculosis is the secretion of virulence factors by various secretion systems (3). There are five different type VII secretion systems (T7SS) in M. tuberculosis (ESX-1 to ESX-5) (4, 5). The different ESX systems were most likely generated via duplications of the ancestral system ESX-4 in the chronological order ESX-1, ESX-3, ESX-2, and ESX-5 (6). All the ESX secretion systems have a set of common genes which encode the core components of their secretion machinery, among which are genes encoding two members of the ESAT-6-like family (Esx proteins) (5, 7).The region of difference 1 (RD1) is a 9.5-kbp stretch comprising 9 genes of ESX-1 that is deleted in all strains of the live tuberculosis vaccine M. bovis BCG (8). The importance of ESX-1 for virulence was first demonstrated by expressing the entire RD1 locus in the BCG vaccine strain and restoring virulence in the mouse model of tuberculosis (9, 10). ESX-1 is essential for full virulence of M. tuberculosis in mice (11-13). In M. marinum, it is required for the growth of bacteria within macrophages, cell-tocell spread, and virulence in the zebrafish model (14). ESX-1 is required for the cosecretion of two ESAT-6 family proteins, EsxA and EsxB (13). The other known substrates are Rv3881c (15) and Rv3864 (16).The ESX-5 system is the most recently evolve...

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Section: Discussionmentioning

confidence: 78%

A Duplicated ESAT-6 Region of ESX-5 Is Involved in Protein Export and Virulence of Mycobacteria

et al. 2015

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“…Recent studies have shown that metabolomics can be used to identify metabolites whose levels are altered in response to an infection (10,(49)(50)(51). In particular, with respect to bacterial infections, the rapid emergence of multidrug-resistant Gram-positive and Gram-negative bacteria fuels the need for novel strategies in diagnosis and treatment (11).…”

Section: Discussionmentioning

confidence: 99%

Global Metabolomic Analysis of a Mammalian Host Infected with Bacillus anthracis

2015

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bWhereas DNA provides the information to design life and proteins provide the materials to construct it, the metabolome can be viewed as the physiology that powers it. As such, metabolomics, the field charged with the study of the dynamic small-molecule fluctuations that occur in response to changing biology, is now being used to study the basis of disease. Here, we describe a comprehensive metabolomic analysis of a systemic bacterial infection using Bacillus anthracis, the etiological agent of anthrax disease, as the model pathogen. An organ and blood analysis identified approximately 400 metabolites, including several key classes of lipids involved in inflammation, as being suppressed by B. anthracis. Metabolite changes were detected as early as 1 day postinfection, well before the onset of disease or the spread of bacteria to organs, which testifies to the sensitivity of this methodology. Functional studies using pharmacologic inhibition of host phospholipases support the idea of a role of these key enzymes and lipid mediators in host survival during anthrax disease. Finally, the results are integrated to provide a comprehensive picture of how B. anthracis alters host physiology. Collectively, the results of this study provide a blueprint for using metabolomics as a platform to identify and study novel host-pathogen interactions that shape the outcome of an infection. Metabolomics, a quickly emerging "omics" field in systems biology, is the global analysis of small molecules in a biological sample (1). Since the 1950s, the central dogma of biological information has been the transition from genes to transcript to protein (2). Only recently has the use of high-throughput systems biology been used to study the products of protein activity, the metabolites. The metabolome represents all endogenous and exogenous low-molecular-mass (Ͻ1-kDa) molecules present in a biological state, providing an instantaneous "snapshot" of the cell's metabolic and physiological activity (3). Applications of global metabolomic analysis fall into three broad categories: (i) disease diagnosis, (ii) biomarker and drug discovery, and (iii) study of metabolic pathways and their perturbations due to external factors (1). The analysis of altered metabolites has the potential for discovery of new biomarkers, thus providing the possibility of earlier intervention and insights into the mechanisms of diseases (4).The diagnosis of a bacterial infection encompasses an assessment of clinical symptoms, positive culture of an organism from tissues or blood, and/or reliance on often expensive, outsourced molecular methods (5). Metabolomics provides a unique perspective on bacterial infections as it is able to comprehensively characterize a vast number of metabolic changes in response to a biological perturbation within the host (2). In addition to the potential for biomarker discovery, the metabolic profiles obtained from this analysis can give insight into the identity and nature of molecules involved in the immune response, detect alterations in ho...

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“…In 2011, Shin et al (86) detected the presence of itaconic acid in the lung tissue of M. tuberculosisinfected mice, but they hypothesized that this metabolite was synthesized by the bacteria and not by the host. Conversely, Michelucci et al (64) …”

Section: Itaconic Acid Inhibits Bacterial Growthmentioning

confidence: 99%

Itaconic Acid: The Surprising Role of an Industrial Compound as a Mammalian Antimicrobial Metabolite

2015

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Itaconic acid is well known as a precursor for polymer synthesis and has been involved in industrial processes for decades. In a recent surprising discovery, itaconic acid was found to play a role as an immune-supportive metabolite in mammalian immune cells, where it is synthesized as an antimicrobial compound from the citric acid cycle intermediate cis-aconitic acid. Although the immune-responsive gene 1 protein (IRG1) has been associated to immune response without a mechanistic function, the critical link to itaconic acid production through an enzymatic function of this protein was only recently revealed. In this review, we highlight the history of itaconic acid as an industrial and antimicrobial compound, starting with its biotechnological synthesis and ending with its antimicrobial function in mammalian immune cells. 12.1

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¹H NMR-based Metabolomic Profiling in Mice Infected with Mycobacterium tuberculosis

Cited by 210 publications

References 54 publications

A Duplicated ESAT-6 Region of ESX-5 Is Involved in Protein Export and Virulence of Mycobacteria

A Duplicated ESAT-6 Region of ESX-5 Is Involved in Protein Export and Virulence of Mycobacteria

Global Metabolomic Analysis of a Mammalian Host Infected with Bacillus anthracis

Itaconic Acid: The Surprising Role of an Industrial Compound as a Mammalian Antimicrobial Metabolite

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1H NMR-based Metabolomic Profiling in Mice Infected with Mycobacterium tuberculosis

Cited by 210 publications

References 54 publications

A Duplicated ESAT-6 Region of ESX-5 Is Involved in Protein Export and Virulence of Mycobacteria

A Duplicated ESAT-6 Region of ESX-5 Is Involved in Protein Export and Virulence of Mycobacteria

Global Metabolomic Analysis of a Mammalian Host Infected with Bacillus anthracis

Itaconic Acid: The Surprising Role of an Industrial Compound as a Mammalian Antimicrobial Metabolite

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¹H NMR-based Metabolomic Profiling in Mice Infected with Mycobacterium tuberculosis