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Leishmania donovani Lipophosphoglycan: Modulation of Macrophage and Dendritic Cell Function
Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Leishmania donovani is a blood-borne tropicial parasite, which infects humans through bites by Phlebotomus sandflies. The parasite survives and multiplies inside macrophages in inner organs, and causes the deadly disease visceral leishmaniasis (Kala-Azar).

Macrophages and dendritic cells (DC) are professional antigen-presenting cells involved in the initiation of immune responses. Immature DC are present in all tissues where they internalise and process antigen, in response to which they migrate from tissue, into draining lymphoid organs, undergo maturation and present antigens to lymphocytes. Control measures for leishmaniasis include testing of new diagnostics and development of affordable and effective vaccines for humans.

Lipophosphoglycan (LPG) is the major surface component of Leishmania donovani promastigotes. LPG comprises a membrane-anchoring lysophosphatidylinositol part and an extracellular chain of disaccharide phosphates. These repetitions are crucial for parasite survival inside macrophages following phagocytosis. LPG has several specific effects on the host cell including inhibition of protein kinase C (PKC) activity, and inhibition of phagosomal maturation, a process requiring depolymerization of periphagosomal F-actin.

Confocal microscopy and image analysis were used to follow F-actin dynamics in single macrophages during phagocytosis of L. donovani promastigotes and LPG-coated particles. F-actin did not depolymerize, but instead progressively polymerized around phagosomes with LPG-containing prey. This correlated with reduced translocation of PKCα to the phagosome and blocked phagosomal maturation. LPG also inhibited cortical actin turnover, which could be the underlying cause of the reduced uptake of LPG-containing prey. Extracellular- and intracellular calcium was necessary for phagocytosis, periphagosomal F-actin breakdown and phagosomal maturation in macrophages interacting with unopsonized prey,and for the action of LPG.

We also studied F-actin turnover in macrophages overexpressing dominant-negative (DN) PKCα. DN PKCα macrophages showed increased amounts of cortical F-actin, decreased phagocytic capacity, inhibition of periphagosomal F-actin breakdown and defective phagosomal maturation. When DN PKCα macrophages interacted with LPG-containing prey, phagocytosis was almost completely blocked.

Moreover, we found that Leishmania promastigotes and particularly LPG inhibit DC maturation and detachment from distinct surfaces. Thus, LPG from Leishmania donovani could directly inhibit DC migration to lymphoid organs, antigen-presentation and development of immunity.

Place, publisher, year, edition, pages
Institutionen för molekylär och klinisk medicin , 2006.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 946
Series
Keyword [en]
Lipophosphoglycan, Leishmania donovani, macrophage, actin, phagocytosis, PKC alpha, dendritic cell
National Category
Pathobiology
Identifiers
URN: urn:nbn:se:liu:diva-6527ISBN: 91-85497-84-3 (print)OAI: oai:DiVA.org:liu-6527DiVA: diva2:21863
Public defence
2006-06-01, Linden, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2006-05-23 Created: 2006-05-23 Last updated: 2009-06-05
List of papers
1. Leishmania donovani lipophosphoglycan causes periphagosomal actin accumulation: correlation with impaired translocation of PKCα and defective phagosome maturation
Open this publication in new window or tab >>Leishmania donovani lipophosphoglycan causes periphagosomal actin accumulation: correlation with impaired translocation of PKCα and defective phagosome maturation
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2001 (English)In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 3, no 7, 439-447 p.Article in journal (Refereed) Published
Abstract [en]

Lipophosphoglycan (LPG) is the major surface glycoconjugate of Leishmania donovani promastigotes. The repeating disaccharide–phosphate units of LPG are crucial for promastigote survival inside macrophages and establishment of infection. LPG has a number of effects on the host cell, including inhibition of PKC activity, inhibition of nitric oxide production and altered expression of cytokines. LPG also inhibits phagosomal maturation, a process requiring depolymerization of periphagosomal F-actin. In the present study, we have characterized the dynamics of F-actin during the phagocytosis of L. donovani promastigotes in J774 macrophages. We observed that F-actin accumulated progressively around phagosomes containing wild-type L. donovani promastigotes during the first hour of phagocytosis. Using LPG-defective mutants and yeast particles coated with purified LPG, we obtained evidence that this effect could be attributed to the repeating units of LPG. LPG also disturbed cortical actin turnover during phagocytosis. The LPG-dependent accumulation of periphagosomal F-actin correlated with an impaired recruitment of the lysosomal marker LAMP1 and PKCα to the phagosome. Accumulation of periphagosomal F-actin during phagocytosis of L. donovani promastigotes may contribute to the inhibition of phagosomal maturation by physically preventing vesicular trafficking to and from the phagosome.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13848 (URN)10.1046/j.1462-5822.2001.00127.x (DOI)
Available from: 2006-05-23 Created: 2006-05-23 Last updated: 2013-09-18Bibliographically approved
2. Phagocytosis and phagosome maturation are regulated by calcium in J774 macrophages interacting with un-opsonized prey
Open this publication in new window or tab >>Phagocytosis and phagosome maturation are regulated by calcium in J774 macrophages interacting with un-opsonized prey
2002 (English)In: Bioscience Reports, ISSN 0144-8463, Vol. 22, no 5-6, 529-540 p.Article in journal (Refereed) Published
Abstract [en]

Phagocytosis by neutrophils, macrophages, and other professional phagocytes requires rapid remodeling of actin. Early phagosomes are surrounded by a rim of F-actin that is disassembled during phagosomoal maturation. Breakdown of periphagosomal F-actin and phagolysosome fusion are calcium dependent processes in neutrophils interacting with serum-opsonized prey, but appears to be calcium independent in macrophages interacting with serum- or IgG-opsonized prey. In the present study, we found that calcium was necessary for phagocytosis, breakdown of periphagosomal F-actin, and phagosomal maturation in J774 macrophages interacting with unopsonized prey. We also observed that lipophosphoglycan (LPG) from Leishmania donovani promastigotes required calcium to exert its inhibitory effect on macrophage phagocytosis and periphagosomal F-actin breakdown. We conclude that calcium is essential for phagocytosis, depolymerization of periphagosomal F-actin, and phagosomal maturation in J774 macrophages interacting with unopsonized prey, as well as for proper functioning of LPG.

Keyword
Macrophage, phagocytosis, calcium, actin, phagosome maturation, lipophosphoglycan
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13849 (URN)10.1023/A:1022025903688 (DOI)
Available from: 2006-05-23 Created: 2006-05-23 Last updated: 2013-09-18
3. Role of protein kinase C α for uptake of unopsonized prey and phagosomal maturation in macrophages
Open this publication in new window or tab >>Role of protein kinase C α for uptake of unopsonized prey and phagosomal maturation in macrophages
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2003 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 302, no 4, 653-658 p.Article in journal (Refereed) Published
Abstract [en]

Protein kinase C α (PKCα) participates in F-actin remodeling during phagocytosis and phagosomal maturation in macrophages. Leishmania donovani promastigotes, which inhibit phagosomal maturation, cause accumulation of periphagosomal F-actin instead of the dissassembly observed around other prey [Cell. Microbiol. 7 (2001) 439]. This accumulation is induced by promastigote lipophosphoglycan (LPG), which has several effects on macrophages including inhibition of PKCα. To investigate a possible connection between PKCα and LPG’s effects on actin dynamics, we utilized RAW264.7 macrophages overexpressing dominant-negative PKCα (DN PKCα). We found increased cortical F-actin and decreased phagocytic capacity, as well as defective periphagosomal F-actin breakdown and inhibited phagosomal maturation in the DN PKCα-overexpressing cells, effects similar to those seen in controls subjected to LPG-coated prey. The results indicate that PKCα is involved in F-actin turnover in macrophages and that PKCα-dependent breakdown of periphagosomal F-actin is required for phagosomal maturation, and endorse the hypothesis that intracellular survival of L. donovani involves inhibition of PKCα by LPG.

Keyword
PKCα, Actin, Phagocytosis, Macrophage, Lipophosphoglycan
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-13850 (URN)10.1016/S0006-291X(03)00231-6 (DOI)
Available from: 2006-05-23 Created: 2006-05-23 Last updated: 2012-10-11Bibliographically approved
4. Leishmania donovani promastigotes block maturation, increase integrin expression and inhibit detachment of human monocytederived dendritic cells – a role for lipophosphoglycan (LPG)
Open this publication in new window or tab >>Leishmania donovani promastigotes block maturation, increase integrin expression and inhibit detachment of human monocytederived dendritic cells – a role for lipophosphoglycan (LPG)
Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-13851 (URN)
Available from: 2006-05-23 Created: 2006-05-23 Last updated: 2010-01-13

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