Living in a phagolysosome; metabolism of Leishmania amastigotes

McConville, Malcolm J.; Souza, David P. De; Saunders, Eleanor; Likić, Vladimir A; Naderer, Thomas

doi:10.1016/j.pt.2007.06.009

Cited by 189 publications

(187 citation statements)

References 78 publications

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“…However, upon commencement of the inflammatory response and accompanying metabolic perturbations, the parasites now find themselves under metabolic conditions more conducive for their growth. It has been proposed recently that the tropism of Leishmania for the macrophage phagolysosome is dependent on that environment being rich in amino acids (62), and our data suggest the possibility that the "richness" of the phagolysosome may vary as the host infection proceeds. Our model also suggests that there may be other Leishmania genes required for growth or survival early versus late in the infection, as the environment experienced by Leishmania within the host macrophage evolves.…”

Section: Discussionsupporting

confidence: 60%

The Role of the Mitochondrial Glycine Cleavage Complex in the Metabolism and Virulence of the Protozoan Parasite Leishmania major

Scott

Hickerson

Vickers

et al. 2008

Journal of Biological Chemistry

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For the human pathogen Leishmania major, a key metabolic function is the synthesis of thymidylate, which requires 5,10-methylenetetrahydrofolate (5,10-CH 2 -THF). 5,10-CH 2 -THF can be synthesized from glycine by the mitochondrial glycine cleavage complex (GCC). Bioinformatic analysis revealed the four subunits of the GCC in the L. major genome, and the role of the GCC in parasite metabolism and virulence was assessed through studies of the P subunit (glycine decarboxylase (GCVP)). First, a tagged GCVP protein was expressed and localized to the parasite mitochondrion. Second, a gcvP ؊ mutant was generated and shown to lack significant GCC activity using an indirect in vivo assay after incorporation of label from [2-14 C]glycine into DNA. The gcvP ؊ mutant grew poorly in the presence of excess glycine or minimal serine; these studies also established that L. major promastigotes require serine for optimal growth. Although gcvP ؊ promastigotes and amastigotes showed normal virulence in macrophage infections in vitro, both forms of the parasite showed substantially delayed replication and lesion pathology in infections of both genetically susceptible or resistant mice. These data suggest that, as the physiology of the infection site changes during the course of infection, so do the metabolic constraints on parasite replication. This conclusion has great significance to the interpretation of metabolic requirements for virulence. Last, these studies call attention in trypanosomatid protozoa to the key metabolic intermediate 5,10-CH 2 -THF, situated at the junction of serine, glycine, and thymidylate metabolism. Notably, genome-based predictions suggest the related parasite Trypanosoma brucei is totally dependent on the GCC for 5,10-CH 2 -THF synthesis.

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Section: Discussionsupporting

confidence: 60%

The Role of the Mitochondrial Glycine Cleavage Complex in the Metabolism and Virulence of the Protozoan Parasite Leishmania major

Scott

Hickerson

Vickers

et al. 2008

Journal of Biological Chemistry

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“…Apart from acting as a safe haven for parasites, the PV provides essential nutrients, cations, and carbon sources for a successful infection. On the other hand, Leishmania is known to salvage low-molecular-weight nutrients (hexoses, amino acids, polyamines, purines, and vitamins) through its membrane transporters while multiplying inside PVs (69). Larger macromolecules such as proteins, carbohydrates, DNA, and RNA are taken up by parasites directly through endocytosis.…”

Section: Resultsmentioning

confidence: 99%

Proteomic-Based Approach To Gain Insight into Reprogramming of THP-1 Cells Exposed to Leishmania donovani over an Early Temporal Window

et al. 2015

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Leishmania has developed an intricate relationship with its host, primarily cells of the monocyte/macrophage lineage, where it exploits and subverts the host immune system by either inducing immunosuppression or promoting proparasitic host factors to ensure its survival and growth in an otherwise harsh milieu (3). Hijacking of innate immune functions of macrophages by Leishmania appears to be a multifarious event, as macrophages have inherently evolved to defend the host against invading pathogens by a myriad of effectors rather than providing a favorable environment to the pathogen. The chief molecular mechanisms by which Leishmania is known to inhibit the activation of macrophages toward its own benefit include suppression of deadly antimicrobial free radicals such as nitric oxide (NO), faulty antigen presentation, selective induction and suppression of host cell apoptosis, inhibition of cytokine production and hence cytokine-inducible macrophage function, and activation of T cells (4-8). Leishmania has evolved sophisticated mechanisms to alter the physiological program and activation of adaptive immune responses of host cells by exploiting host cell signaling mechanisms such as the downregulation of Ca 2ϩ -dependent classical protein kinase C (PKC) activity and extracellular signal-regulated kinase (ERK) phosphorylation and activity (9, 10). Using mainly host tyrosine phosphatases, Leishmania is known to deactivate mitogen-activated protein kinases (MAPKs) in infected macrophages (5). Extensive manipulations of host cell effector (innate and adaptive) functions by pathogens must be reflected at the levels of transcripts as well as proteins. Enormous efforts made in the field of host gene expression profiling using different (murine and/or human) cell types and different species of Leishmania provide key insights into an extensive modulation of gene function and contribute to a better understanding of the dynamics of gene expres-

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“…They multiply in the low-pH, amino acid-rich endolysosomes, to which their metabolism and nutrition are adapted (30). L. donovani and L. infantum, which infect cells found in lymphoid tissues, including spleen, lymph nodes, and bone marrow, inhibit an effective immune response to the parasite.…”

Section: Figurementioning

confidence: 99%

Kinetoplastids: related protozoan pathogens, different diseases

Stuart¹,

Brun²,

Croft³

et al. 2008

J. Clin. Invest.

501

515

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Kinetoplastids are a group of flagellated protozoans that include the species Trypanosoma and Leishmania, which are human pathogens with devastating health and economic effects. The sequencing of the genomes of some of these species has highlighted their genetic relatedness and underlined differences in the diseases that they cause. As we discuss in this Review, steady progress using a combination of molecular, genetic, immunologic, and clinical approaches has substantially increased understanding of these pathogens and important aspects of the diseases that they cause. Consequently, the paths for developing additional measures to control these "neglected diseases" are becoming increasingly clear, and we believe that the opportunities for developing the drugs, diagnostics, vaccines, and other tools necessary to expand the armamentarium to combat these diseases have never been better.

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Living in a phagolysosome; metabolism of Leishmania amastigotes

Cited by 189 publications

References 78 publications

The Role of the Mitochondrial Glycine Cleavage Complex in the Metabolism and Virulence of the Protozoan Parasite Leishmania major

The Role of the Mitochondrial Glycine Cleavage Complex in the Metabolism and Virulence of the Protozoan Parasite Leishmania major

Proteomic-Based Approach To Gain Insight into Reprogramming of THP-1 Cells Exposed to Leishmania donovani over an Early Temporal Window

Kinetoplastids: related protozoan pathogens, different diseases

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