Underestimated Manipulative Roles of Mycobacterium tuberculosis Cell Envelope Glycolipids During Infection

Garcia-Vilanova, Andreu; Chan, John; Torrelles, Jordi B.

doi:10.3389/fimmu.2019.02909

Cited by 54 publications

(69 citation statements)

References 225 publications

(221 reference statements)

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“…Consistent with this hypothesis, we have shown that FasR is necessary for optimal intracellular multiplication of M. tuberculosis in macrophages, therefore confirming the role of cell wall components in the ability of the pathogen to survive and multiply intracellularly (Garcia-Vilanova et al, 2019). In addition, the lack of FasR impaired the normal in vitro replication of M. tuberculosis in minimal medium devoid of lipids.…”

Section: Discussionsupporting

confidence: 83%

FasR Regulates Fatty Acid Biosynthesis and Is Essential for Virulence of Mycobacterium tuberculosis

et al. 2020

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Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is the world's leading cause of death from an infectious disease. One of the main features of this pathogen is the complex and dynamic lipid composition of the cell envelope, which adapts to the variable host environment and defines the fate of infection by actively interacting with and modulating immune responses. However, while much has been learned about the enzymes of the numerous lipid pathways, little knowledge is available regarding the proteins and metabolic signals regulating lipid metabolism during M. tuberculosis infection. In this work, we constructed and characterized a FasR-deficient mutant in M. tuberculosis and demonstrated that FasR positively regulates fas and acpS expression. Lipidomic analysis of the wild type and mutant strains revealed complete rearrangement of most lipid components of the cell envelope, with phospholipids, mycolic acids, sulfolipids, and phthiocerol dimycocerosates relative abundance severely altered. As a consequence, replication of the mutant strain was impaired in macrophages leading to reduced virulence in a mouse model of infection. Moreover, we show that the fasR mutant resides in acidified cellular compartments, suggesting that the lipid perturbation caused by the mutation prevented M. tuberculosis inhibition of phagolysosome maturation. This study identified FasR as a novel factor involved in regulation of mycobacterial virulence and provides evidence for the essential role that modulation of lipid homeostasis plays in the outcome of M. tuberculosis infection.

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Section: Discussionsupporting

confidence: 83%

FasR Regulates Fatty Acid Biosynthesis and Is Essential for Virulence of Mycobacterium tuberculosis

et al. 2020

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“…Consistent with this hypothesis, we have shown that FasR is necessary for optimal intracellular multiplication of M. tuberculosis in macrophages, therefore confirming the role of cell wall components in the ability of the pathogen to survive and multiply intracellularly (Garcia-Vilanova et al, 2019). Persistence of the tubercle bacillus inside cells relies upon inhibition of phagosome maturation and acidification (Rohde et al, 2007).…”

Section: Discussionsupporting

confidence: 75%

FasR regulates fatty acid biosynthesis and is essential for virulence ofMycobacterium tuberculosis

Mondino

Vázquez

Cabruja

et al. 2020

Preprint

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30 31 Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is the 32 world's leading cause of death from an infectious disease. One of the main 33 features of this pathogen is the complex and dynamic lipid composition of the cell 34 envelope, which adapts to the variable host environment and defines the fate of 35 infection by actively interacting with and modulating immune responses. Fine 36 regulation of de novo fatty acid biosynthesis, and its interaction with other 37 peripheral lipid pathways, is essential for cell membrane homeostasis while quickly 38 adapting to the growth environment. However, while much has been learned about 39 the enzymes of the numerous lipid pathways present in M. tuberculosis, little 40 knowledge is available regarding the proteins and metabolic signals regulating lipid 41 metabolism during infection. Previous studies on the regulation of lipid biosynthesis 42 in mycobacteria identified FasR as an essential transcriptional activator of de novo 43 fatty acid biosynthesis in Mycobacterium smegmatis. In this work, we constructed 44 and characterized a FasR-deficient mutant in M. tuberculosis and demonstrated 45 that FasR positively regulates fas and acpS expression. Lipidomic analysis of the 46 wild type and mutant strains revealed complete rearrangement of most lipid 47 components of the cell envelope, with phospholipids, mycolic acids, sulfolipids and 48 phthiocerol dimycocerosates relative abundance severely altered. As a 49 consequence, replication of the mutant strain was impaired in macrophages 50 leading to reduced virulence in a mouse model of infection. Moreover, we show 51 that the fasR mutant resides in acidified cellular compartments, suggesting that the 3 52 lipid perturbation caused by the mutation prevented M. tuberculosis inhibition of 53 phagolysosome maturation. This study identified FasR as a novel factor involved in 54 regulation of mycobacterial virulence and provides evidence for the essential role 55 that modulation of lipid homeostasis plays in the outcome of M. tuberculosis 56 infection. 57 58 Author summary 59 60 Tuberculosis is the leading cause of death from a single infectious disease, 61 resulting in approximately 1.5 million deaths per year worldwide. The composition 62 and complexity of the cell envelope is the most distinctive feature of 63 Mycobacterium tuberculosis, the etiologic agent of human tuberculosis. As the 64 mycobacterial cell envelope is the interface with the host, the modulation of its 65 structure and consequent responsiveness to immune factors might be important in 66 determining the state of an infection. We have previously identified FasR as an 67 essential transcriptional activator of de novo fatty acid biosynthesis in 68 Mycobacterium smegmatis. In this study, a M. tuberculosis mutant strain in fasR 69 was constructed and analyzed. Inactivation of fasR in M. tuberculosis was not 70 lethal for in vitro growth but led to rearrangement of the lipid composition of the cell 71 envelope. Consequently, the mutant strain w...

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“…The recruitment of the early endosome autoantigen (EEA1) protein to early phagosomes is an essential step in phagosome maturation that Mtb LAM is able to inhibit (Fratti et al, 2001). These excellent reviews provide a more in-depth overview on the activity of PIM/LM/LAM Mtb glycolipids (Vergne et al, 2014;Garcia-Vilanova et al, 2019).…”

Section: Pim Lm Lammentioning

confidence: 99%

“…This group of Mtb lipids is composed of the trehalose-containing lipids (Garcia-Vilanova et al, 2019). Probably the best known lipid within this group is the essential lipid trehalose dimycolate (TDM), also called "cord factor" because it is required for the cording phenotype of Mtb which was originally described by Robert Koch in 1882 (Glickman et al, 2000).…”

Section: Tdm Dat/pat Sl-1mentioning

confidence: 99%

“…Accordingly, Mtb mutants which have a deficiency of cycloprane modification in the mycolic acid chains of TDM show a defect in cording and a decrease in the granulomatous response in vivo, as well as the persistence in the host (Glickman et al, 2000;Rao et al, 2005). A second group of compounds are the di-/ poly-acyltrehaloses (DAT/PAT) (Garcia-Vilanova et al, 2019). They have no effect on virulence of Mtb in the mouse and guinea pig model (Rousseau et al, 2003a;Chesne-Seck et al, 2008;Passemar et al, 2014) but in the absence of PDIM a role in virulence could be detected for DAT/PAT in the mouse model (Passemar et al, 2014).…”

Section: Tdm Dat/pat Sl-1mentioning

confidence: 99%

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Host Cell Targets of Released Lipid and Secreted Protein Effectors of Mycobacterium tuberculosis

Augenstreich

Briken

2020

Front. Cell. Infect. Microbiol.

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Mycobacterium tuberculosis (Mtb) is a very successful pathogen, strictly adapted to humans and the cause of tuberculosis. Its success is associated with its ability to inhibit host cell intrinsic immune responses by using an arsenal of virulence factors of different nature. It has evolved to synthesize a series of complex lipids which form an outer membrane and may also be released to enter host cell membranes. In addition, secreted protein effectors of Mtb are entering the host cell cytosol to interact with host cell proteins. We briefly discuss the current model, involving the ESX-1 type seven secretion system and the Mtb lipid phthiocerol dimycoserosate (PDIM), of how Mtb creates pores in the phagosomal membrane to allow Mtb proteins to access to the host cell cytosol. We provide an exhaustive list of Mtb secreted proteins that have effector functions. They modify (mostly inhibit but sometimes activate) host cell pathways such as: phagosome maturation, cell death, cytokine response, xenophagy, reactive oxygen species (ROS) response via NADPH oxidase 2 (NOX2), nitric oxide (NO) response via NO Synthase 2 (NOS2) and antigen presentation via MHC class I and class II molecules. We discuss the host cell targets for each lipid and protein effector and the importance of the Mtb effector for virulence of the bacterium.

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Underestimated Manipulative Roles of Mycobacterium tuberculosis Cell Envelope Glycolipids During Infection

Cited by 54 publications

References 225 publications

FasR Regulates Fatty Acid Biosynthesis and Is Essential for Virulence of Mycobacterium tuberculosis

FasR Regulates Fatty Acid Biosynthesis and Is Essential for Virulence of Mycobacterium tuberculosis

FasR regulates fatty acid biosynthesis and is essential for virulence ofMycobacterium tuberculosis

Host Cell Targets of Released Lipid and Secreted Protein Effectors of Mycobacterium tuberculosis

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