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1.
Curr Opin Microbiol ; 63: 126-132, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34340099

RESUMO

Leishmania are unusual in being able to survive long-term in the mature phagolysosome compartment of macrophages and other phagocytic cells in their mammalian hosts. Key to their survival in this niche, Leishmania amastigotes switch to a slow growth state and activate a stringent metabolic response. The stringent metabolic response may be triggered by multiple stresses and is associated with decreased metabolic fluxes, restricted use of sugars and fatty acids as carbon sources and increased dependence on metabolic homeostasis pathways. Heterogeneity in expression of the Leishmania stringent response occurs in vivo reflects temporal and spatial heterogeneity in lesion tissues and includes non-dividing dormant stages. This response underpins the capacity of these parasites to maintain long-term chronic infections and survive drug treatments.


Assuntos
Leishmania , Parasitos , Animais , Ácidos Graxos , Leishmania/genética , Macrófagos , Fagossomos
2.
Trends Parasitol ; 37(11): 988-1001, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34266735

RESUMO

Nearly all eukaryotic cells synthesize carbohydrate reserves, such as glycogen, starch, or low-molecular-weight oligosaccharides. However, a number of parasitic protists have lost this capacity while others have lost, and subsequently evolved, entirely new pathways. Recent studies suggest that retention, loss, or acquisition of these pathways in different protists is intimately linked to their lifestyle. In particular, parasites with carbohydrate reserves often establish long-lived chronic infections and/or produce environmental cysts, whereas loss of these pathways is associated with parasites that have highly proliferative and metabolically active life-cycle stages. The evolution of mannogen biosynthesis in Leishmania and related parasites indicates that these pathways have played a role in defining the host range and niches occupied by some protists.


Assuntos
Leishmania , Parasitos , Animais , Carboidratos , Eucariotos , Estágios do Ciclo de Vida , Parasitos/metabolismo
3.
PLoS Negl Trop Dis ; 8(12): e3402, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25521752

RESUMO

Parasitic protozoa, such as Leishmania species, are thought to express a number of surface and secreted nucleoside triphosphate diphosphohydrolases (NTPDases) which hydrolyze a broad range of nucleoside tri- and diphosphates. However, the functional significance of NTPDases in parasite virulence is poorly defined. The Leishmania major genome was found to contain two putative NTPDases, termed LmNTPDase1 and 2, with predicted NTPDase catalytic domains and either an N-terminal signal sequence and/or transmembrane domain, respectively. Expression of both proteins as C-terminal GFP fusion proteins revealed that LmNTPDase1 was exclusively targeted to the Golgi apparatus, while LmNTPDase2 was predominantly secreted. An L. major LmNTPDase1 null mutant displayed increased sensitivity to serum complement lysis and exhibited a lag in lesion development when infections in susceptible BALB/c mice were initiated with promastigotes, but not with the obligate intracellular amastigote stage. This phenotype is characteristic of L. major strains lacking lipophosphoglycan (LPG), the major surface glycoconjugate of promastigote stages. Biochemical studies showed that the L. major NTPDase1 null mutant synthesized normal levels of LPG that was structurally identical to wild type LPG, with the exception of having shorter phosphoglycan chains. These data suggest that the Golgi-localized NTPase1 is involved in regulating the normal sugar-nucleotide dependent elongation of LPG and assembly of protective surface glycocalyx. In contrast, deletion of the gene encoding LmNTPDase2 had no measurable impact on parasite virulence in BALB/c mice. These data suggest that the Leishmania major NTPDase enzymes have potentially important roles in the insect stage, but only play a transient or non-major role in pathogenesis in the mammalian host.


Assuntos
Antígenos CD/fisiologia , Apirase/fisiologia , Glicoesfingolipídeos/metabolismo , Complexo de Golgi/enzimologia , Leishmania major/patogenicidade , Animais , Antígenos CD/genética , Apirase/genética , Proteínas do Sistema Complemento/imunologia , Feminino , Leishmania major/metabolismo , Leishmaniose Cutânea/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Virulência
4.
PLoS One ; 8(2): e56064, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23437085

RESUMO

Leishmania are protozoan parasites that proliferate within the phagolysome of mammalian macrophages. While a number of anti-oxidant systems in these parasites have been shown to protect against endogenous as well as host-generated reactive oxygen species, the potential role of enzymes involved in the repair of oxidatively damaged proteins remains uncharacterized. The Leishmania spp genomes encode a single putative methionine sulfoxide reductase (MsrA) that could have a role in reducing oxidized free and proteinogenic methionine residues. A GFP-fusion of L. major MsrA was shown to have a cytoplasmic localization by immunofluorescence microscopy and subcellular fractionation. An L. major msrA null mutant, generated by targeted replacement of both chromosomal allelles, was viable in rich medium but was unable to reduce exogenous methionine sulfoxide when cultivated in the presence of this amino acid, indicating that msrA encodes a functional MsrA. The ΔmsrA mutant exhibited increased sensitivity to H(2)O(2) compared to wild type parasites and was unable to proliferate normally in macrophages. Wild type sensitivity to H(2)O(2) and infectivity in macrophages was restored by complementation of the mutant with a plasmid encoding MsrA. Unexpectedly, the ΔmsrA mutant was able to induce normal lesions in susceptible BALB/c indicating that this protein is not essential for pathogenesis in vivo. Our results suggest that Leishmania MsrA contributes to the anti-oxidative defences of these parasites, but that complementary oxidative defence mechansims are up-regulated in lesion amastigotes.


Assuntos
Leishmania major/enzimologia , Leishmania major/crescimento & desenvolvimento , Macrófagos/parasitologia , Metionina Sulfóxido Redutases/metabolismo , Estresse Oxidativo , Sequência de Aminoácidos , Animais , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Citoplasma/efeitos dos fármacos , Citoplasma/parasitologia , Modelos Animais de Doenças , Deleção de Genes , Genes de Protozoários/genética , Proteínas de Fluorescência Verde/metabolismo , Peróxido de Hidrogênio/farmacologia , Leishmania major/citologia , Leishmania major/genética , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Macrófagos/efeitos dos fármacos , Espectrometria de Massas , Metionina/análogos & derivados , Metionina/metabolismo , Metionina Sulfóxido Redutases/genética , Camundongos , Dados de Sequência Molecular , Estresse Oxidativo/efeitos dos fármacos , Parasitos/citologia , Parasitos/efeitos dos fármacos , Parasitos/enzimologia , Transporte Proteico/efeitos dos fármacos , Alinhamento de Sequência , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo
5.
J Biol Chem ; 278(42): 40757-63, 2003 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-12902334

RESUMO

The protozoan parasite Leishmania mexicana proliferates within macrophage phagolysosomes in the mammalian host. In this study we provide evidence that a novel class of intracellular beta1-2 mannan oligosaccharides is important for parasite survival in host macrophages. Mannan (degree of polymerization 4-40) is expressed at low levels in non-pathogenic promastigote stages but constitutes 80 and 90% of the cellular carbohydrate in the two developmental stages that infect macrophages, non-dividing promastigotes, and lesion-derived amastigotes, respectively. Mannan is catabolized when parasites are starved of glucose, suggesting a reserve function, and developmental stages having low mannan levels or L. mexicana GDPMP mutants lacking all mannose molecules are highly sensitive to glucose starvation. Environmental stresses, such as mild heat shock or the heat shock protein-90 inhibitor, geldanamycin, that trigger the differentiation of promastigotes to amastigotes, result in a 10-25-fold increase in mannan levels. Developmental stages with low mannan levels or L. mexicana mutants lacking mannan do not survive heat shock and are unable to differentiate to amastigotes or infect macrophages in vitro. In contrast, a L. mexicana mutant deficient only in components of the mannose-rich surface glycocalyx differentiates normally and infects macrophages in vitro. Collectively, these data provide strong evidence that mannan accumulation is important for parasite differentiation and survival in macrophages.


Assuntos
Leishmania/patogenicidade , Mananas/química , Fatores de Virulência/química , Animais , Benzoquinonas , Divisão Celular , Cromatografia Líquida de Alta Pressão , Citosol/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Glicocálix/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas , Macrófagos/metabolismo , Macrófagos/parasitologia , Camundongos , Mutação , Oligossacarídeos/química , Quinonas/farmacologia , Frações Subcelulares/metabolismo , Fatores de Tempo
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