Mycobacterium leprae intracellular survival relies on cholesterol accumulation in infected macrophages: a potential target for new drugs for leprosy treatment. (21st March 2014)

• Record Type: Journal Article
• Authors: Mattos, Katherine A.; Oliveira, Viviane C. G.; Berrêdo‐Pinho, Marcia; Amaral, Julio J.; Antunes, Luis Caetano M.; Melo, Rossana C. N.; Acosta, Chyntia C. D.; Moura, Danielle F.; Olmo, Roberta; Han, Jun; Rosa, Patricia S.; Almeida, Patrícia E.; Finlay, B. Brett; Borchers, Christoph H.; Sarno, Euzenir N.; Bozza, Patricia T.; Atella, Georgia C.; Pessolani, Maria Cristina V.
• Is Part Of: Cellular microbiology. Volume 16:Number 6(2014:Jun.)
• Page Start: 797
• Page End: 815
• Publication Date: 2014-03-21
• Subjects: Microbiology -- Periodicals; Cytology -- Periodicals; Host-parasite relationships -- Periodicals; Microbiology -- Periodicals; Cells -- Periodicals; Microbiologie -- Périodiques; Microbiologie; Relation hôte-parasite; Cytologie; Cellule; Réponse cellulaire; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); 579.05
• DOI: 10.1111/cmi.12279
• Languages: English
• ISSNs: 1462-5814

Abstract

<abstract abstract-type="main"> <title>Summary</title> <p>We recently showed that <italic>M</italic><italic>ycobacterium leprae</italic> (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 <italic>in vitro</italic> 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 <italic>de novo</italic> 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.</p> </abstract>