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Leishmania donovani: Inhibition of phagosomal maturation is rescued by nitric oxide in macrophages
Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
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, Medical Microbiology .
2007 (English)In: Experimental parasitology, ISSN 0014-4894, Vol. 117, no 2, 165-170 p.Article in journal (Refereed) Published
Abstract [en]

Leishmania donovani promastigotes, the causative agent of visceral leishmaniasis, survive inside macrophages by inhibiting phagosomal maturation. The main surface glycoconjugate on promastigotes, lipophosphoglycan (LPG), is crucial for parasite survival. LPG has several detrimental effects on macrophage function, including inhibition of periphagosomal filamentous actin (F-actin) breakdown during phagosomal maturation. However, in RAW 264.7 macrophages pre-stimulated with lipopolysaccharide (LPS) and interferon ? (IFN?), known to up-regulate inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production, L. donovani promastigotes are unable to inhibit periphagosomal F-actin breakdown and phagosomal maturation proceeds normally. Moreover, the iNOS inhibitor aminoguanidine, blocked the positive effects of LPS/IFN? suggesting that NO is a key player in F-actin remodeling. In conclusion, production of NO by stimulated macrophages seems to allow phagosomal maturation following uptake of L. donovani promastigotes, suggesting a novel mechanism whereby NO facilitates killing of an intracellular pathogen. © 2007 Elsevier Inc. All rights reserved.

Place, publisher, year, edition, pages
2007. Vol. 117, no 2, 165-170 p.
Keyword [en]
Actin, AG, aminoguanidine, bovine serum albumine, BSA, cGMP, F-actin, filamentous actin, gamma Interferon, GFP, green fluorescent protein, guanosine 3':5'-cyclic monophosphate, IFN?, inducible nitric oxide synthase, iNOS, Leishmania donovani, lipophosphoglycan, lipopolysaccharide, LPG, LPS, Maturation, Nitric oxide, nitric oxide, NO, paraformaldehyde, PFA, Phagosome
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-48433DOI: 10.1016/j.exppara.2007.04.004OAI: diva2:269329
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2009-12-14Bibliographically 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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