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1.
Mol Biochem Parasitol ; 172(2): 80-9, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20307588

RESUMO

Leishmania parasites, the causative agent of leishmaniasis, have a digenetic lifecycle consisting of the morphologically distinct insect vector stage (promastigote) and the mammalian infective amastigote stage. Differentiation of promastigotes to the amastigote stage involves significant morphological and biochemical changes, however, very few genes have been characterised as being differentially expressed in the two stages. The Leishmania A600 genes are one of the few gene families that exhibit stage-specific expression and, as such, they are of interest as potential virulent factors. In this study, we characterize the A600 family in several Leishmania species and investigate their role in amastigote differentiation and proliferation. Four open reading frames, A600-1, A600-2, A600-3, and A600-4, were identified at the multi-gene L. mexicana A600 locus via cloning and restriction mapping. Homology searching identified A600 homologues in other Leishmania species, L. major, L. braziliensis and L. infantum but not in the closely related Trypanosoma family. A targeted gene deletion approach was utilized to determine the cellular function of the L. mexicanaA600 genes. A600(-/-) promastigotes differentiated to axenic amastigotes in response to temperature shift and acidification of culture media, but showed significant growth arrest. Similarly, during in vitro macrophage infection studies, A600(-/-) promastigotes established an early infection, but were deficient in their ability to proliferate as intracellular amastigotes. The ability of A600(-/-) amastigotes to proliferate in mouse peritoneal macrophages was restored by re-introduction of the A600-1 gene, but not the A600-4 gene. The results from these experiments show that the A600-1 gene is essential for continued proliferation of amastigotes, and potentially for development of chronic leishmaniasis. Furthermore, these results suggest a potential role for the L. mexicana A600-deficient mutant as a vaccine candidate.


Assuntos
Regulação da Expressão Gênica , Genes de Protozoários , Leishmania mexicana/crescimento & desenvolvimento , Leishmania mexicana/genética , Animais , Clonagem Molecular , Deleção de Genes , Teste de Complementação Genética , Leishmania braziliensis/genética , Leishmania infantum/genética , Leishmania major/genética , Macrófagos Peritoneais/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Fases de Leitura Aberta , Mapeamento por Restrição , Trypanosoma/genética , Virulência
2.
Mol Biochem Parasitol ; 153(2): 125-32, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17433460

RESUMO

Protozoan parasites of the genus Leishmania have a digenetic lifecycle, alternating between the promastigote and amastigote stages. The extracellular promastigote resides within a sandfly vector, while the obligate intracellular amastigote stage replicates in the phagolysosome of mammalian host macrophages. Adaptation to and survival within these vastly differently environments is accompanied by differential expression of a subset of genes, which is regulated post-transcriptionally via cis-acting elements in 3' untranslated region (3'UTR) or intercistronic sequences. It was reported previously that Leishmania mexicana A600-4 mRNA transcript abundance was eight-fold higher in the amastigotes. In this study, chimeric luciferase:A600-4 3'UTR reporter constructs were integrated at the A600 chromosome locus to identify regulatory regions of the A600-4 3'UTR sequence. Evidence is provided for distinct 3'UTR elements that function to stabilize the A600-4 mRNA transcript in the amastigote stage and to regulate translation efficiency, respectively.


Assuntos
Regiões 3' não Traduzidas/química , Regulação da Expressão Gênica no Desenvolvimento , Leishmania mexicana/crescimento & desenvolvimento , Estágios do Ciclo de Vida , Biossíntese de Proteínas , Regiões 3' não Traduzidas/genética , Animais , Genes Reporter , Leishmania mexicana/genética , Leishmania mexicana/metabolismo , Luciferases/genética , Luciferases/metabolismo , Dados de Sequência Molecular , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA de Protozoário/genética , RNA de Protozoário/metabolismo , Análise de Sequência de DNA
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