Role of Membrane Cholesterol in Leishmanial Infection

Chattopadhyay, Amitabha; Jafurulla, Md.

doi:10.1007/978-1-4614-3381-1_14

Cited by 20 publications

(9 citation statements)

References 67 publications

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“…An effective way to achieve this is to reduce (or block) host membrane cholesterol. This approach has been successfully tried for entry of pathogens such as Leishmania [9,20,21,36,45,47,48,55] and Mycobacterium [12,20,57]. An advantage of such therapeutic approach involving modulation of host membrane cholesterol provides The energy landscape corresponding to the interaction of cholesterol with specific sites on the receptor surface involves a series of shallow minima connected by low energy barriers of the order of kT at room temperature.…”

Section: Role Of Host Membrane Cholesterol In Pathogen Entrymentioning

confidence: 99%

Cholesterol: An evergreen molecule in biology

Kumar

Chattopadhyay

2016

BSI

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Abstract. Cholesterol, an essential component of higher eukaryotic membranes, was discovered more than two centuries ago. The development and progress of cholesterol research in the last 200 years has been truly fascinating, with elements of surprise, serendipity and intrigue. In this review, we trace this journey the way we see it, and follow it up with the role of membrane cholesterol in crucial areas of contemporary research (transbilayer domains, regulation of GPCR function and role in the entry of intracellular pathogens into host cells), with considerable footprint from our work. We believe that cholesterol will continue to surprise and fascinate future researchers, thereby justifying its evergreen nature. Keywords: Membrane cholesterol, transbilayer dimer, G protein-coupled receptor, pathogen entry Abbreviations 7-DHC7-dehydrocholesterol 7-DHCR 3β-hydroxy-steroid-7 -reductase 25-NBD-cholesterol 25-[N-[(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-methyl]amino]-27-norcholesterol CRAC cholesterol recognition/interaction amino acid consensus DHE dehydroergosterol ( 5,7,9(11)22 -ergostatetraen-3β-ol) DPPC 1,2-dipalmitoyl-sn-glycero-3-phosphocholine FRAP fluorescence recovery after photobleaching GPCR G protein-coupled receptor NBD 7-nitrobenz-2-oxa-1,3-diazol-4-yl REES red edge excitation shift SLOS Smith-Lemli-Opitz syndrome

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Section: Role Of Host Membrane Cholesterol In Pathogen Entrymentioning

confidence: 99%

Cholesterol: An evergreen molecule in biology

Kumar

Chattopadhyay

2016

BSI

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“…A hallmark of membrane cholesterol is its nonrandom distribution in domains (or pools) in biological and model membranes [25–28]. These domains are believed to be crucial since various cellular processes such as membrane sorting and trafficking [29], signal transduction [30], and the entry of pathogens [31,32] have been attributed to these types of domains. The role of cholesterol in the function and organization of membrane proteins and receptors constitutes an emerging and exciting area of research [10–14].…”

Section: Introductionmentioning

confidence: 99%

Stereospecific requirement of cholesterol in the function of the serotonin1A receptor

Jafurulla

Rao

Sugunan

et al. 2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The serotonin1A receptor is an important member of the G protein-coupled receptor (GPCR) family. It is involved in the generation and modulation of a variety of cognitive and behavioral functions, and serves as a drug target. Previous work from our laboratory has established the sensitivity of the function of the serotonin1A receptor to membrane cholesterol. Solubilization of the hippocampal serotonin1A receptor utilizing the zwitterionic detergent CHAPS is accompanied by loss of cholesterol and results in reduction in specific ligand binding. Replenishment of cholesterol to solubilized membranes restores specific ligand binding to the receptor. We utilized this strategy of sterol replenishment of solubilized membranes to explore the stereospecific stringency of cholesterol for receptor function. We used two stereoisomers of cholesterol, ent-cholesterol (enantiomer of cholesterol) and epi-cholesterol (a diastereomer of cholesterol) for this purpose. Importantly, we show here that while ent-cholesterol could replace cholesterol in supporting receptor function, epi-cholesterol could not. These results imply that the requirement of membrane cholesterol for the serotonin1A receptor function is diastereospecific, yet not enantiospecific. Our results extend and help define specificity of the interaction of membrane cholesterol with the serotonin1A receptor, and represent the first report utilizing ent-cholesterol to examine stereospecificity of GPCR-cholesterol interaction.

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“…A number of studies have indicated the crucial requirement of membrane cholesterol in host-pathogen interaction (recently reviewed in [9]). In this overall scenario, we previously demonstrated the requirement of membrane cholesterol in infection by Leishmania donovani [16,17,21] and Mycobacterium smegmatis [37].…”

Section: Discussionmentioning

confidence: 99%

“…vector while taking a blood meal from a host [8]. Leishmania exists in two distinct forms through its lifecycle; the flagellated extracellular promastigote form that subsequently transforms into aflagellated amastigote form within host cells [4,9]. Entry of Leishmania into host macrophages involves multiple parasite-host interactions, and recognition of specific ligands on the parasite cell surface by receptors on the macrophage cell surface [8,10,11].…”

Section: Introductionmentioning

confidence: 99%

Statin-induced chronic cholesterol depletion inhibits Leishmania donovani infection: Relevance of optimum host membrane cholesterol

Kumar

Roy

Jafurulla

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Leishmania are obligate intracellular protozoan parasites that invade and survive within host macrophages leading to leishmaniasis, a major cause of mortality and morbidity worldwide, particularly among economically weaker sections in tropical and subtropical regions. Visceral leishmaniasis is a potent disease caused by Leishmania donovani. The detailed mechanism of internalization of Leishmania is poorly understood. A basic step in the entry of Leishmania involves interaction of the parasite with the host plasma membrane. In this work, we have explored the effect of chronic metabolic cholesterol depletion using lovastatin on the entry and survival of Leishmania donovani in host macrophages. We show here that chronic cholesterol depletion of host macrophages results in reduction in the attachment of Leishmania promastigotes, along with a concomitant reduction in the intracellular amastigote load. These results assume further relevance since chronic cholesterol depletion is believed to mimic physiological cholesterol modulation. Interestingly, the reduction in the ability of Leishmania to enter host macrophages could be reversed upon metabolic replenishment of cholesterol. Importantly, enrichment of host membrane cholesterol resulted in reduction in the entry and survival of Leishmania in host macrophages. As a control, the binding of Escherichia coli to host macrophages remained invariant under these conditions, thereby implying specificity of cholesterol requirement for effective leishmanial infection. To the best of our knowledge, these results constitute the first comprehensive demonstration that an optimum content of host membrane cholesterol is necessary for leishmanial infection. Our results assume relevance in the context of developing novel therapeutic strategies targeting cholesterol-mediated leishmanial infection.

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Role of Membrane Cholesterol in Leishmanial Infection

Cited by 20 publications

References 67 publications

Cholesterol: An evergreen molecule in biology

Cholesterol: An evergreen molecule in biology

Stereospecific requirement of cholesterol in the function of the serotonin1A receptor

Statin-induced chronic cholesterol depletion inhibits Leishmania donovani infection: Relevance of optimum host membrane cholesterol

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