Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Multiple levels of gene regulation mediate differentiation of the intracellular pathogen Leishmania

ABSTRACT: Whole genome high density tiliing array of eight timepoints from the promastitgote to amastigote differentiation process. RNA from two independent biological replicates from eight points in the promastigote to amastigote differentiation process were hybridized to Nimblegen arrays (Madison,WI USA) that contained 10 probes per open reading frame and 3 probes per structural RNA spotted three times per array. The microarray probes were designed to Leishmania infantum strain JCPM5 and the sample RNA was obtained from Leishmania donovani strain S1. The two species are thought to be nearly identical at the nucleotide level, however whole-genome sequence was not available from L. donovani.

ORGANISM(S): Leishmania donovani

SUBMITTER: Dhileep Sivam

PROVIDER: E-GEOD-21936 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Protozoa of the genus Leishmania are the causative agents of leishmaniasis in humans. These parasites cycle between promastigotes in the sand fly mid-gut and amastigotes in phagolysosome of mammalian macrophages. During infection, host up-regulate nitric oxide synthase and parasite induce host arginase expression, both of which use arginine as a substrate. These elevated activities deplete macrophage arginine pools, a situation that invading Leishmania must overcome since it is an essential amino acid. Leishmania donovani imports exogenous arginine via a mono-specific amino acid transporter (AAP3) and utilizes it primarily through the polyamine pathway to provide precursors for trypanothione biosynthesis. Here we report the discovery of a pathway whereby promastigote and amastigote forms of the Leishmania sense the lack of environmental arginine and respond with rapid up-regulation in AAP3 expression and activity, as well as several other transporters. Significantly, this arginine deprivation response is also activated in parasites during macrophage infection. Phosphoproteomic analyses of L. donovani promastigotes have implicated a Mitogen-Activated Protein Kinase 2 (MPK2)-mediated signaling cascade in this response and L. mexicana mutants lacking MPK2 are unable to respond to arginine deprivation. In this study, we established that Leishmania cells sense the absence of arginine in their environment; both in culture (axenic promastigotes and amastigotes) and in macrophages during infection (amastigotes). This study describes the first amino acid deprivation sensing mechanism and the pathway that transduce this response, and reveals a novel host-pathogen metabolic interplay. Total RNA from Ten Leishmania donovani samples were analyzed using RNA-Seq. Cells from two life stages (promastigotes and amastigotes) were grown in axenic culture in the presence and absense of arginine. For each condition two biological replicates were grown and analyzed. In addition two macrophage grown amastigotes were analyzed.

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Multiple levels of gene regulation mediate differentiation of the intracellular pathogen Leishmania

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