Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Leishmania major modulates autophagy in host macrophages during intracellular differentiation

ABSTRACT: Autophagy generally participates in innate immunity by elimination of intracellular pathogens. However, many of them developed successful strategies to counteract their autolysosomal digestion and lastly to exploit this catabolic cellular process. Protozoan parasites of the genus Leishmania are the causative agent of leishmaniasis, one of the 13 most important tropical diseases. Leishmania persists as endo-parasite in host macrophages, where it uses multiple strategies to manipulate the microbicidal host cell functions and to escape from the host immune system. Understanding how Leishmania interacts with host macrophages during uptake, differentiation, intracellular replication, and release might be the key to develop new drugs in target-directed approaches to treat patient with leishmaniasis. Here, we generated expression profiles from bone marrow-derived macrophages (BMDM) at 1h and 24h post infection (p.i.) with Leishmania major and respective controls.

ORGANISM(S): Mus musculus

SUBMITTER: Claus Scholz

PROVIDER: E-GEOD-52624 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Autophagic digestion of Leishmania major by host macrophages is associated with differential expression of BNIP3, CTSE, and the miRNAs miR-101c, miR-129, and miR-210.

Frank Benjamin B Marcu Ana A de Oliveira Almeida Petersen Antonio Luis AL Weber Heike H Stigloher Christian C Mottram Jeremy C JC Scholz Claus Juergen CJ Schurigt Uta U

Parasites & vectors 20150731

<h4>Background</h4>Autophagy participates in innate immunity by eliminating intracellular pathogens. Consequently, numerous microorganisms have developed strategies to impair the autophagic machinery in phagocytes. In the current study, interactions between Leishmania major (L. m.) and the autophagic machinery of bone marrow-derived macrophages (BMDM) were analyzed.<h4>Methods</h4>BMDM were generated from BALB/c mice, and the cells were infected with L. m. promastigotes. Transmission electron mi ...[more]

PMID: 26226952

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Project description:Leishmania donovani, an intracellular protozoan parasite, is the causative agent of visceral leishmaniasis or kala-azar, the most severe form of leishmaniasis in humans. To date, our understanding of the molecular mechanisms associated with the pathogenicity of Leishmania infection is still limited. RNA interference—collectively RNA silencing pathways—participates in the regulation of various biological processes in most eukaryotic cells. Complexes of Argonaute proteins with small RNAs are core components of the RNA interference system and play a key role in silencing gene expression. It is becoming increasingly clear that several intracellular pathogens target host cell RNA interference pathways to promote their survival. In this study, we investigated the potential role of host macrophage Argonautes in Leishmania pathogenesis. Western blot analysis showed that protein abundance of infected macrophage Argonaute 1 (Ago1) was selectively and significantly higher than that of non-infected control at 24 h post-infection, suggesting that Ago1 plays a role in pathogenicity. In fact, siRNA-mediated downregulation of Ago1 enhanced Leishmania clearance from infected host cells, linking macrophage Ago1 to Leishmania virulence. To investigate the mechanisms of host Ago1 in Leishmania pathogenesis, a stable isotope labeling by amino acids in cell culture (SILAC)-based whole proteome approach was employed, which showed that expression of several previously reported Leishmania pathogenesis-related proteins were dependent on the level of macrophage Ago1. Moreover, the proteomic-based detailed biochemical analysis showed that Leishmania modulated host RNA-induced silencing complex (RISC) composition during infection, strongly suggesting macrophage RISC targeting. Strikingly, Leishmania proteins were detected as part of host RISC in infected cells. Together, our results demonstrate that Leishmania targets host RNA interference machinery to promote its survival inside the host macrophage.

Dataset Information

Leishmania major modulates autophagy in host macrophages during intracellular differentiation

Publications

Autophagic digestion of Leishmania major by host macrophages is associated with differential expression of BNIP3, CTSE, and the miRNAs miR-101c, miR-129, and miR-210.

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