Cholesterol is required for Leishmania donovani infection: implications in leishmaniasis

Pucadyil, Thomas J.; Tewary, Poonam; Madhubala, Rentala; Chattopadhyay, Amitabha

doi:10.1016/j.molbiopara.2003.10.002

Cited by 111 publications

(86 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…2c). These observations are consistent with a role for lipid microdomains in the phagocytic process in general and in the internalization of L. donovani promastigotes (Pucadyil et al, 2004;Rodríguez et al, 2006). Moreover, these results are consistent with the hypothesis that insertion into and disorganization of lipid microdomains by LPG (Dermine et al, 2005;Vinet et al, 2009;Winberg et al, 2009) may reduce the phagocytic capacity of macrophages.…”

Section: Internalization Of L Donovani Promastigotes Requires Intactsupporting

confidence: 90%

Exclusion of synaptotagmin V at the phagocytic cup by Leishmania donovani lipophosphoglycan results in decreased promastigote internalization

Vinet¹,

Jananji²,

Turco

et al. 2011

Microbiology

View full text Add to dashboard Cite

Regulators of membrane fusion play an important role in phagocytosis, as they regulate the focal delivery of endomembrane that is required for optimal internalization of large particles. During internalization of Leishmania promastigotes, the surface glycolipid lipophosphoglycan (LPG) is transferred to the macrophage membrane and modifies its fusogenic properties. In this study, we investigated the impact of LPG on the recruitment of the exocytosis regulator synaptotagmin V (Syt V) at the area of internalization and on the early steps of phagocytosis. Using Leishmania donovani LPG-defective mutants and LPG-coated particles, we established that LPG reduces the phagocytic capacity of macrophages and showed that it causes exclusion of Syt V from the nascent phagosome. Silencing of Syt V inhibited phagocytosis to the same extent as LPG, and these effects were not cumulative, consistent with a Syt V-dependent mechanism for the inhibition of phagocytosis by LPG. Previous work has revealed that LPG-mediated exclusion of Syt V from phagosomes prevents the recruitment of the vacuolar ATPase and acidification. Thus, whereas exclusion of Syt V from phagosomes in the process of formation may be beneficial for the creation of a hospitable intracellular niche, it reduces the phagocytic capacity of macrophages. We propose that the cost associated with a reduced internalization rate may be compensated by increased survival, and could lead to a greater overall parasite fitness. INTRODUCTIONThe various species of the protozoan parasite Leishmania are responsible for a spectrum of human diseases ranging from a relatively confined cutaneous lesion to a progressive visceral infection that can be fatal. Transmission of the parasite is mediated by blood-sucking sandflies, either of the genus Phlebotomus or of the genus Lutzomyia. Upon the bloodmeal of an infected sandfly, infectious promastigotes are inoculated into the mammalian host, where they are phagocytosed by macrophages. Promastigotes subsequently differentiate into amastigotes and replicate within phagolysosomal vacuoles (Alexander & Russell, 1992).Internalization of Leishmania promastigotes is a classical receptor-mediated endocytic event involving multiple Leishmania and macrophage surface molecules. On macrophages, the complement receptors 1 and 3, the mannose receptor p150,95, DC-SIGN, and the scavenger receptors have been implicated in promastigote binding, although their relative roles in internalization remain to be firmly established (Akilov et al., 2007;Colmenares et al., 2004;Gomes et al., 2009;Mosser, 1994). Two major Leishmania promastigote surface components have been shown to participate in the attachment process. One is the glycosylphosphatidylinositol (GPI)-anchored metalloprotease gp63, which acts as a primary acceptor for C3 deposition on the promastigote surface (Brittingham et al., 1995;Russell, 1987). The second is lipophosphoglycan (LPG), an abundant virulence-related surface glycolipid consisting of a polymer of Galb(1,4(-Man(a1)-PO 4 units anchored int...

show abstract

Section: Internalization Of L Donovani Promastigotes Requires Intactsupporting

confidence: 90%

Exclusion of synaptotagmin V at the phagocytic cup by Leishmania donovani lipophosphoglycan results in decreased promastigote internalization

Vinet¹,

Jananji²,

Turco

et al. 2011

Microbiology

View full text Add to dashboard Cite

show abstract

“…However, the study demonstrated that macrophage-depleted lipids decreased their ability to interact with Leishmania donovani and internalize promastigotes by 45%, thus impairing the replication of the parasite. On the other hand, when depleted macrophages are treated with cholesterol, there is an increased chance that the parasites will destroy the cell membrane 39 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition to playing an important role in the maintenance of membrane fl uidity, cholesterol is essential for the proper function of antigen presenting cells and is also a prognostic indicator of increased morbidity and mortality associated with pathological conditions [34][35][36] . This lipid is responsible for the formation of membrane rafts, which are essential for Leishmania entry [37][38][39] . In malnourished animals infected with Leishmania chagasi, decreases in serum albumin, globulin and total protein were observed, and these changes were associated with an increased parasite burden and a non-response to the vaccine 40 .…”

Section: Methodsmentioning

confidence: 99%

Biochemical and nutritional evaluation of patients with visceral leishmaniasis before and after treatment with leishmanicidal drugs

Gatto

Abreu

Tasca

et al. 2013

Rev. Soc. Bras. Med. Trop.

View full text Add to dashboard Cite

Revista da Sociedade Brasileira de Medicina Tropical 46(6):735-740, Nov-Dec, 2013http://dx.doi.org/10.1590/0037-8682-0198-2013 ABSTRACT Introduction: Visceral leishmaniasis (VL) is caused by the intracellular protozoan Leishmania donovani complex. VL may be asymptomatic or progressive and is characterized by fever, anemia, weight loss and the enlargement of the spleen and liver. The nutritional status of the patients with VL is a major determinant of the progression, severity and mortality of the disease, as it affects the clinical progression of the disease. Changes in lipoproteins and plasma proteins may have major impacts in the host during infection. Thus, our goal was evaluate the serum total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, glucose, albumin, globulin and total protein levels, as well as the body composition, of VL patients before and after treatment. Methods: Nutritional evaluation was performed using the bioelectrical impedance analysis (BIA) to assess body composition. Biochemical data on the serum total cholesterol, HDL, LDL, triglycerides, glucose, albumin, globulin and total protein were collected from the medical charts of the patients. Results: BIA indicated that both pre-treatment and post-treatment patients exhibited decreased phase angles compared to the controls, which is indicative of disease. Prior to treatment, the patients exhibited lower levels of total body water compared to the controls. Regarding the biochemical evaluation, patients with active VL exhibited lower levels of total cholesterol, HDL, LDL and albumin and higher triglyceride levels compared to patients after treatment and the controls. Treatment increased the levels of albumin and lipoproteins and decreased the triglyceride levels. Conclusions: Our results suggest that patients with active VL present biochemical and nutritional changes that are reversed by treatment. INTRODUCTION

show abstract

“…Pucadyil et al [31] found that cholesterol depletion resulted in reduced uptake of unopsonized WT L. donovani promastigotes while phagocytosis of opsonized promastigotes and Escherichia coli remained unaffected. This suggests that the receptor(s) responsible for internalization of unopsonized promastigotes are localized to membrane rafts, or depend on intact rafts for function.…”

Section: Discussionmentioning

confidence: 99%

Leishmania donovani lipophosphoglycan inhibits phagosomal maturation via action on membrane rafts

Winberg

Holm

Särndahl

et al. 2009

Microbes and Infection

View full text Add to dashboard Cite

Lipophosphoglycan (LPG), the major surface glycoconjugate on Leishmania donovani promastigotes, is crucial for the establishment of infection inside macrophages. LPG comprises a polymer of repeating Galβ1,4Manα-PO 4 attached to a lysophosphatidylinositol membrane anchor. LPG is transferred from the parasite to the host macrophage membrane during phagocytosis and induces periphagosomal F-actin accumulation correlating with an inhibition of phagosomal maturation. The biophysical properties of LPG suggest that it may be intercalated into membrane rafts of the host cell membrane. The aim of this study was to investigate if the effects of LPG on phagosomal maturation are mediated via action on membrane rafts. We show that LPG accumulates in rafts during phagocytosis of L. donovani and that disruption of membrane rafts abolished the effects of LPG on periphagosomal F-actin and phagosomal maturation, indicating that LPG requires intact membrane rafts to manipulate host cell functions. We conclude that LPG associates with membrane rafts in the host cell and exert its actions on host-cell actin and phagosomal maturation through subversion of raft function.2 3

show abstract

Cholesterol is required for Leishmania donovani infection: implications in leishmaniasis

Cited by 111 publications

References 36 publications

Exclusion of synaptotagmin V at the phagocytic cup by Leishmania donovani lipophosphoglycan results in decreased promastigote internalization

Exclusion of synaptotagmin V at the phagocytic cup by Leishmania donovani lipophosphoglycan results in decreased promastigote internalization

Biochemical and nutritional evaluation of patients with visceral leishmaniasis before and after treatment with leishmanicidal drugs

Leishmania donovani lipophosphoglycan inhibits phagosomal maturation via action on membrane rafts

Contact Info

Product

Resources

About