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Roles of calcium and annexins in phagocytosis and elimination of an attenuated strain of Mycobacterium tuberculosisin human neutrophils
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Division of Infectious Diseases and Rosalind Russell Research Laboratory, University of California, San Francisco and San Francisco General Hospital, San Francisco, CA, U.S.A..
Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
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1998 (English)In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 24, no 5, 309-320 p.Article in journal (Refereed) Published
Abstract [en]

The phagocytic function of neutrophils is a crucial element in the host defence against invading microorganisms. We investigated phagocytosis and intracellular killing of an attenuated strain of Mycobacterium tuberculosis(H37Ra) by human neutrophils focusing on the role of the cytosolic free calcium concentration [Ca2+]iand certain cytosolic calcium-dependent membrane-binding proteins annexins. Phagocytic uptake did not trigger a calcium rise and occurred independently of different calcium conditions, and in a serum-dependent manner. Changes in the viability of H37Ra were determined by agar plate colony count and a radiometric assay. Neutrophils showed a capacity to kill ingested mycobacteria and this occurred without a rise in [Ca2+]i. The ability to kill H37Ra decreased in the absence of extracellular calcium and when intra-extracellular calcium was reduced. Immunofluorescence staining revealed that during phagocytosis of H37Ra, annexins III, IV and VI translocated from cytoplasm to the proximity of the H37Ra-containing phagosomes, whereas the localization of annexin I and V remained unchanged. The translocation of annexin IV occurred even when Ca2+-depleted neutrophils ingested H37Ra in the absence of extracellular calcium. We concluded that neutrophil-mediated killing of mycobacteria is a Ca2+-dependent process. The fact that the association of certain annexins to the membrane vesicle containing H37Ra differ from other phagosomes suggests a selective regulatory mechanism during phagocytosis of mycobacteria by neutrophils.

Place, publisher, year, edition, pages
1998. Vol. 24, no 5, 309-320 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-81105DOI: 10.1006/mpat.1997.0200OAI: oai:DiVA.org:liu-81105DiVA: diva2:550464
Available from: 2012-09-07 Created: 2012-09-07 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Interaction Between Mycobacterium tuberculosis and Human Neutrophils
Open this publication in new window or tab >>Interaction Between Mycobacterium tuberculosis and Human Neutrophils
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is responsible for more deaths each year than any other single pathogen. Mononuclear phagocytes and T cells are crucially involved in the control and local containment of this infection. Less is known about the contribution of neutrophils to control tuberculosis. As one of the most efficient phagocytic cells of the immune system, neutrophils restrict the initial, local replication of numerous pathogens and thereby delay their systemic spread. Neutrophils immigrate quickly to the site of mycobacterial entry and are found in granulomas after infection with M. tuberculosis. The aims of this study were to investigate how neutrophils control M. tuberculosis in the acute phase of mycobacterial infection and the signaling pathways regulating these processes.

When neutrophils are exposed to mycobacteria, they exhibit the typical early bactericidal responses: phagocytosis, generation of reactive oxygen intermediate (ROI), degranulation and the killing of mycobacteria. While production of ROI and M. tuberculosis killing in neutrophils are calcium dependent events, phagocytosis of M. tuberculosis is a calcium-independent process. Measuring intracellular calcium concentration [(Ca+2)]i, revealed that there is no increase in the level of [(Ca+2)]i in single neutrophils upon ingestion of M. tuberculosis. Investigation of the M. tuberculosis-induced phagocytic pathway showed that stimulation of neutrophils by M. tuberculosis triggers tyrosine phosphorylation of PLCγ2 and its association with sch, an adapter protein, and that such association are critical for the M. tuberculosis-stimulated ROI production through activating p38 MAPK. During phagolysosome biogenesis, phagosomes containing M. tuberculosis fused sequentially with secondary granule and late endosomal vacuoles, while delivery of azurophil granule was inhibited. A complex of Rab5a-GTP and syntaxin-4 controlled this fusion process. We suggested that the retention of this complex on the mycobacterial phagosome might allow mycobacteria to avoid the usual physiological destination of phagocytic maturation. Neutrophils infected by M. tuberculosis underwent rapid apoptosis that was mediated by activation of caspase-3 and the expression of Bax and Bcl-x1, two antagonizing members of Bcl-2 family. The level of ROI production controlled this M. tuberculosis induced apoptotic pathway. Apoptotic neutrophils are removed by macrophages, which leads to an augmented mycobactericidal effect in these cells. The results from this work show that neutrophils play an efficient and important role in the early innate immune response against mycobacterial infection, a process that may influence the subsequent specific immune response at the site of infection.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2001. 71 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 679
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-28623 (URN)13779 (Local ID)91-7219-964-4 (ISBN)13779 (Archive number)13779 (OAI)
Public defence
2001-05-31, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-09-07Bibliographically approved

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Majeed, MeythamPerskvist, NasrinOrselius, KristinaStendahl, Olle

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