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Leishmania donovani targets Dicer1 to downregulate miR-122, lower serum cholesterol, and facilitate murine liver infection.

ABSTRACT: Leishmania donovani causes visceral leishmaniasis (VL) where the parasite infects and resides inside liver and spleen tissue macrophages. Given the abnormal lipid profile observed in VL patients, we examined the status of serum lipids in an experimental murine model of VL. The murine VL liver displayed altered expression of lipid metabolic genes, many of which are direct or indirect targets of the liver-specific microRNA-122. Concomitant reduction of miR-122 expression was observed in VL liver. High serum cholesterol caused resistance to L. donovani infection, while downregulation of miR-122 is coupled with low serum cholesterol in VL mice. Exosomes secreted by the infective parasites caused reduction in miR-122 activity in hepatic cells. Leishmania surface glycoprotein gp63, a Zn-metalloprotease, targets pre-miRNA processor Dicer1 to prevent miRNP formation in L. donovani-interacting hepatic cells. Conversely, restoration of miR-122 or Dicer1 levels in VL mouse liver increased serum cholesterol and reduced liver parasite burden.

SUBMITTER: Ghosh J

PROVIDER: S-EPMC3605572 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Leishmania donovani targets Dicer1 to downregulate miR-122, lower serum cholesterol, and facilitate murine liver infection.

Ghosh June J Bose Mainak M Roy Syamal S Bhattacharyya Suvendra N SN

Cell host & microbe 20130301 3

Leishmania donovani causes visceral leishmaniasis (VL) where the parasite infects and resides inside liver and spleen tissue macrophages. Given the abnormal lipid profile observed in VL patients, we examined the status of serum lipids in an experimental murine model of VL. The murine VL liver displayed altered expression of lipid metabolic genes, many of which are direct or indirect targets of the liver-specific microRNA-122. Concomitant reduction of miR-122 expression was observed in VL liver. ...[more]

PMID: 23498953

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Project description:Nucleoside hydrolases of the Leishmania genus are vital enzymes for the replication of the DNA and conserved phylogenetic markers of the parasites. Leishmania donovani nucleoside hydrolase (NH36) induced a main CD4(+) T cell driven protective response against L. chagasi infection in mice which is directed against its C-terminal domain. In this study, we used the three recombinant domains of NH36: N-terminal domain (F1, amino acids 1-103), central domain (F2 aminoacids 104-198), and C-terminal domain (F3 amino acids 199-314) in combination with saponin and assayed their immunotherapeutic effect on Balb/c mice previously infected with L. amazonensis. We identified that the F1 and F3 peptides determined strong cross-immunotherapeutic effects, reducing the size of footpad lesions to 48 and 64%, and the parasite load in footpads to 82.6 and 81%, respectively. The F3 peptide induced the strongest anti-NH36 antibody response and intradermal response (IDR) against L. amazonenis and a high secretion of IFN-γ and TNF-α with reduced levels of IL-10. The F1 vaccine, induced similar increases of IgG2b antibodies and IFN-γ and TNF-α levels, but no IDR and no reduction of IL-10. The multiparameter flow cytometry analysis was used to assess the immune response after immunotherapy and disclosed that the degree of the immunotherapeutic effect is predicted by the frequencies of the CD4(+) and CD8(+) T cells producing IL-2 or TNF-α or both. Total frequencies and frequencies of double-cytokine CD4 T cell producers were enhanced by F1 and F3 vaccines. Collectively, our multifunctional analysis disclosed that immunotherapeutic protection improved as the CD4 responses progressed from 1+ to 2+, in the case of the F1 and F3 vaccines, and as the CD8 responses changed qualitatively from 1+ to 3+, mainly in the case of the F1 vaccine, providing new correlates of immunotherapeutic protection against cutaneous leishmaniasis in mice based on T-helper TH1 and CD8(+) mediated immune responses.

Dataset Information

Leishmania donovani targets Dicer1 to downregulate miR-122, lower serum cholesterol, and facilitate murine liver infection.

Publications

Leishmania donovani targets Dicer1 to downregulate miR-122, lower serum cholesterol, and facilitate murine liver infection.

Similar Datasets

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