Mycobacterium leprae intracellular survival relies on cholesterol accumulation in infected macrophages: a potential target for new drugs for leprosy treatment
| Autor: | Patrícia Sammarco Rosa, Katherine Antunes de Mattos, Patrícia E. Almeida, Roberta Olmo, Julio J. Amaral, Viviane Carneiro Gonçalves Oliveira, Chyntia Carolina Diaz Acosta, Rossana C. N. Melo, Marcia Berrêdo-Pinho, B. Brett Finlay, Luis Caetano M. Antunes, Euzenir Nunes Sarno, Maria Cristina Vidal Pessolani, Georgia C. Atella, Christoph H. Borchers, Patrícia T. Bozza, Danielle F. Moura, Jun Han |
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| Rok vydání: | 2013 |
| Předmět: |
endocrine system
CD36 Immunology Blotting Western Biology Real-Time Polymerase Chain Reaction Microbiology 03 medical and health sciences Western blot Virology Lipid droplet Leprosy Phagosomes medicine Animals Humans Editor’S Choice Mycobacterium leprae Cells Cultured 030304 developmental biology Sterol Regulatory Element Binding Proteins 0303 health sciences Lepromatous leprosy Microbial Viability medicine.diagnostic_test 030306 microbiology Gene Expression Profiling Macrophages medicine.disease biology.organism_classification Molecular biology 3. Good health Sterol regulatory element-binding protein Mice Inbred C57BL Cholesterol Biochemistry Receptors LDL LDL receptor Host-Pathogen Interactions biology.protein lipids (amino acids peptides and proteins) Intracellular |
| Zdroj: | Cellular Microbiology |
| ISSN: | 1462-5822 |
| Popis: | We recently showed that Mycobacterium leprae (ML) is able to induce lipid droplet formation in infected macrophages. We herein confirm that cholesterol (Cho) is one of the host lipid molecules that accumulate in ML-infected macrophages and investigate the effects of ML on cellular Cho metabolism responsible for its accumulation. The expression levels of LDL receptors (LDL-R, CD36, SRA-1, SR-B1, and LRP-1) and enzymes involved in Cho biosynthesis were investigated by qRT-PCR and/or Western blot and shown to be higher in lepromatous leprosy (LL) tissues when compared to borderline tuberculoid (BT) lesions. Moreover, higher levels of the active form of the sterol regulatory element-binding protein (SREBP) transcriptional factors, key regulators of the biosynthesis and uptake of cellular Cho, were found in LL skin biopsies. Functional in vitro assays confirmed the higher capacity of ML-infected macrophages to synthesize Cho and sequester exogenous LDL-Cho. Notably, Cho colocalized to ML-containing phagosomes, and Cho metabolism impairment, through either de novo synthesis inhibition by statins or depletion of exogenous Cho, decreased intracellular bacterial survival. These findings highlight the importance of metabolic integration between the host and bacteria to leprosy pathophysiology, opening new avenues for novel therapeutic strategies to leprosy. |
| Databáze: | OpenAIRE |
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