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Leishmania donovani lipophosphoglycan inhibits phagosomal maturation via action on membrane rafts
Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
INRS, Canada.
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2009 (English)In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 11, no 2, 215-222 p.Article in journal (Refereed) Published
Abstract [en]

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 Gal beta 1,4Man alpha-PO4 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.

Place, publisher, year, edition, pages
2009. Vol. 11, no 2, 215-222 p.
Keyword [en]
Leishmania, Lipophosphoglycan, Membrane rafts, Phagosomal maturation, Actin
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-17886DOI: 10.1016/j.micinf.2008.11.007OAI: diva2:212948

Original Publication: Martin Winberg Tinnerfelt, Åsa Holm, Eva Särndahl, Adrien F Vinet, Albert Descoteaux, Karl-Eric Magnusson, Birgitta Rasmusson and Maria Lerm, Leishmania donovani lipophosphoglycan inhibits phagosomal maturation via action on membrane rafts, 2009, MICROBES AND INFECTION, (11), 2, 215-222. Copyright: Elsevier Science B.V., Amsterdam.

Available from: 2009-05-20 Created: 2009-04-24 Last updated: 2014-01-13Bibliographically approved
In thesis
1. Leukocyte responses to pathogens: integrins, membrane rafts and nitric oxide
Open this publication in new window or tab >>Leukocyte responses to pathogens: integrins, membrane rafts and nitric oxide
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

During microbial invasion, leukocytes of the innate immunity are rapidly recruited to the site of infection where they internalize (phagocytose), kill and digest the invaders. To aid this process, leukocytes express surface receptors such as Toll-like receptors, β2-integrins and Fc-receptors. The β2-integrins are also used for attachment to the extracellular matrix and are important for migration. When pro- vs. anti-inflammatory regulation of β2-integrins was investigated, it was found that chemotactic factors modulate neutrophil adhesion through altered affinity and/or avidity of β2-integrins. A bacteria-derived chemoattractant evoked a large increase in affinity as well as in mobility and clustering, while an early, host-derived chemotactic factor induced increased clustering and surface mobility, but only a slight increase in affinity. Anti-inflammatory lipoxin affected β2-integrin avidity, but not affinity.

The leukocyte membrane is composed of lipids and proteins, which are inhomogeneously distributed. Specific domains in the membrane, membrane rafts, are enriched in signaling proteins and receptors. It was found that lipophosphoglycan (LPG) a virulence factor and membrane component of the parasite Leishmania donovani, accumulated in macrophage rafts during infection, inhibited PKCα translocation to the membrane and halted phagosomal maturation. Membrane rafts were instrumental for LPG to exert its effect. We further showed that nitric oxide (NO) rescued phagosomal maturation halted by Leishmania donovani parasites, possibly through effects on actin dynamics. NO did not affect parasite virulence per se. Moreover, lipoarabinomannan (LAM), a virulence factor on Mycobacterium tuberculosis (Mtb) bacteria, also inserted itself into macrophage membrane rafts. LAM from a less virulent strain (PILAM) was less efficiently inserted. Insertion could to some extent be inhibited by phosphatidylinositol mannoside (PIM), another structural molecule from Mtb. LAM did not activate the p38 MAPK signaling pathway nor did LAM interfere with TLR 2 or 4 signaling. In neutrophil leukocytes we observed a simultaneous, calciumdependent up-regulation of membrane rafts and secretion of azurophilic granules at the site of phagocytosis. Rafts were also found in the phagosome membrane. Wild type Streptococcus pyogenes bacteria, which can survive phagocytosis, modulated raft delivery.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2008. 63 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1058
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
urn:nbn:se:liu:diva-43383 (URN)73683 (Local ID)978-91-7393-921-8 (ISBN)73683 (Archive number)73683 (OAI)
Public defence
2008-05-28, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2015-11-19Bibliographically approved

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Winberg Tinnerfelt, MartinHolm, ÅsaSärndahl, EvaMagnusson, Karl-EricRasmusson, BirgittaLerm, Maria
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