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  • 51.
    Schön, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Elias, D.
    Microbiology and Tumour Biology Centre, Karolinska Institute, Stockholm, Sweden and Armauer Hansen Research Institute (AHRI), Addis Ababa.
    Moges, F.
    Gondar College of Medical Sciences (GCMS), Gondar, Ethiopia .
    Melese, E.
    Gondar College of Medical Sciences (GCMS), Gondar, Ethiopia .
    Tessema, T.
    Gondar College of Medical Sciences (GCMS), Gondar, Ethiopia .
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Britton, Sven
    Dept of Infectious Diseases, Karolinska Hospital, Stockholm.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis2003In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 21, no 3, p. 483-488Article in journal (Refereed)
    Abstract [en]

    Nitric oxide (NO) is involved in the host defence against tuberculosis (TB). Patients with TB exhibit increased catabolism and reduced energy intake. Thus the hypothesis for this study was that restoring a relative deficiency in the amino acid arginine, the substrate for mycobactericidal NO production, would improve the clinical outcome of TB by increasing NO production.

    In a randomised double-blind study, patients with smear-positive TB (n=120) were given arginine or placebo for 4 weeks in addition to conventional chemotherapy. Primary outcomes were sputum conversion, weight gain, and clinical symptoms after week 8. Secondary outcomes were sedimentation rate and levels of NO metabolites, arginine, citrulline, and tumour necrosis factor‐α.

    Compared with the human immunodeficiency virus (HIV)−/TB+ placebo group, the HIV−/TB+ patients in the arginine group showed significant improvement, defined as increased weight gain, higher sputum conversion rate and faster reduction of symptoms, such as cough. The arginine level increased after week 2 in the HIV−/TB+ arginine group (100.2 µM (range 90.5–109.9) versus 142.1 µM (range 114.1–170.1)) compared with the HIV−/TB+ placebo group (105.5 µM (range 93.7–117.3) versus 95.7 µM (range 82.4–108.9)). HIV seroprevalence was 52.5%. No clinical improvement or increase in serum arginine was detected in arginine supplemented HIV+/TB+ patients compared with placebo.

    Arginine is beneficial as an adjuvant treatment in human immunodeficiency virus-negative patients with active tuberculosis, most likely mediated by increased production of nitric oxide.

  • 52.
    Schön, Thomas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Idh, Jonna
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Westman, A
    Karolinska Hospital.
    Elias, D
    Armauer Hansen Research Institute.
    Abate, E
    Armauer Hansen Res Instititute.
    Diro, E
    Gondar University.
    Moges, F
    Gondar University.
    Kassu, A
    Gondar University.
    Ayele, B
    Gondar University.
    Forslund, Tony
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Getachew, A
    Gondar University.
    Britton, S
    Karolinska Hospital.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Effects of a food supplement rich in arginine in patients with smear positive pulmonary tuberculosis - A randomised trial2011In: Tuberculosis, ISSN 1472-9792, E-ISSN 1873-281X, Vol. 91, no 5, p. 370-377Article in journal (Refereed)
    Abstract [en]

    In tuberculosis (TB), the production of nitric oxide (NO) is confirmed but its importance in host defense is debated. Our aim was to investigate whether a food supplement rich in arginine could enhance clinical improvement in TB patients by increased NO production. Smear positive TB patients from Gondar, Ethiopia (n = 180) were randomized to a food supplementation rich in arginine (peanuts, equivalent to 1 g of arginine/day) or with a low arginine content (wheat crackers, locally called daboqolo) during four weeks. The primary outcome was cure rate according to the WHO classification and secondary outcomes were sputum smear conversion, weight gain, sedimentation rate, reduction of cough and chest X-ray improvement as well as levels of NO in urine (uNO) or exhaled air (eNO) at two months. There was no effect of the intervention on the primary outcome (OR 1.44, 95% CI: 0.69-3.0, p = 0.39) or secondary outcomes. In the subgroup analysis according to HIV status, peanut supplemented HIV+/TB patients showed increased cure rate (83.8% (31/37) vs 53.1% (17/32), p andlt; 0.01). A low baseline eNO (andlt; 10 ppb) in HIV+/TB patients was associated with a decreased cure rate. We conclude that nutritional supplementation with a food supplement rich in arginine did not have any overall clinical effect. In the subgroup of HIV positive TB patients, it significantly increased the cure rate and as an additional finding in this subgroup, low initial levels of NO in exhaled air were associated with a poor clinical outcome but this needs to be confirmed in further studies.

  • 53.
    Schön, Thomas
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Wolday, Dawit
    Elias, Daniel
    Melese, Endalkachew
    Mogens, Feleke
    Tessema, Tesfaye
    Stendahl, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Sundqvist, Tommy
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Britton, Sven
    Kinetics of sedimentation rate, viral load and TNF-α in relation to HIV co-infection in tuberculosis2006In: Transactions of the Royal Society of Tropical Medicine and Hygiene, ISSN 0035-9203, E-ISSN 1878-3503, Vol. 100, no 5, p. 483-488Article in journal (Refereed)
    Abstract [en]

    The kinetics of potential surrogate markers in HIV-positive (HIV+) and HIV-negative (HIV-), smear-positive tuberculosis (Tb+) patients in Gondar, Ethiopia (n = 60) was investigated. Clinical symptoms, sputum conversion, sedimentation rate (SR), HIV viral load and serum levels of TNF-α were determined before and 8 weeks after treatment initiation. The co-infection rate of HIV was 45%. There were significantly higher initial levels of SR and TNF-α in HIV+/Tb+ patients (79 ± 29 mm/h and 13.5 ± 7.6 pg/ml), than in HIV-/Tb+ patients (60 ± 23 mm/h and 6.8 ± 5.9 pg/ml, P < 0.001). In HIV-/Tb+ patients, there was a marked decrease in SR compared with co-infected patients (46% [33 ± 24 mm/h at week 8] vs. 24% [61 ± 27 mm/h at week 8]). The HIV viral load (4.99 [range 3.70-5.92] to 4.90 [range 3.96-5.78] log10 copies/ml from week 0 to 8) and TNF-α (13.5 ± 7.6 to 12.0 ± 6.0 pg/ml) remained high in HIV+/Tb+ patients. In Tb patients, SR was significantly increased in HIV+ compared with HIV- patients. Additionally, TNF-α and HIV viral load remained elevated in HIV+/ Tb+ patients following treatment despite clinical improvement comparable to HIV-/Tb+ patients. © 2005 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

  • 54.
    Serrander, Lena
    et al.
    Divison of Infectious Diseases, University of Geneva, Switzerland.
    Jerström Skarman, Petra
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Rasmusson, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Witke, Walter
    European Molecular Biology Laboratory Mouse Biology Program, Monterotondo, Italy.
    Lew, Daniel P.
    Divison of Infectious Diseases, University of Geneva, Switzerland.
    Krause, Karl-Heinz
    Divison of Infectious Diseases, University of Geneva, Switzerland.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Nüße, Oliver
    Divison of Infectious Diseases, University of Geneva, Switzerland.
    Selective Inhibition of IgG-Mediated Phagocytosis in Gelsolin-Deficient Murine Neutrophils2000In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 165, no 5, p. 2451-2457Article in journal (Refereed)
    Abstract [en]

    Phagocytosis and the microbicidal functions of neutrophils require dynamic changes of the actin cytoskeleton. We have investigated the role of gelsolin, a calcium-dependent actin severing and capping protein, in peripheral blood neutrophils from gelsolin-null (Gsn) mice. The phagocytosis of complement opsonized yeast was only minimally affected. In contrast, phagocytosis of IgG-opsonized yeast was reduced close to background level in Gsn neutrophils. Thus, gelsolin is essential for efficient IgG- but not complement-mediated phagocytosis. Furthermore, attachment of IgG-opsonized yeast to Gsn neutrophils was reduced (∼50%) but not to the same extent as ingestion (∼73%). This was not due to reduced surface expression of the Fcγ-receptor or its lateral mobility. This suggests that attachment and ingestion of IgG-opsonized yeast by murine neutrophils are actin-dependent and gelsolin is important for both steps in phagocytosis. We also investigated granule exocytosis and several steps in phagosome processing, namely the formation of actin around the phagosome, translocation of granules, and activation of the NADPH-oxidase. All these functions were normal in Gsn neutrophils. Thus, the role of gelsolin is specific for IgG-mediated phagocytosis. Our data suggest that gelsolin is part of the molecular machinery that distinguishes complement and IgG-mediated phagocytosis. The latter requires a more dynamic reorganization of the cytoskeleton.

  • 55.
    Serrander, Lena
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Larsson, Jenny
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Lundqvist, Helen
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Lindmark, Maria
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Fällman, Maria
    Department of Medical Microbiology, University of Umeå, Umeå, Sweden.
    Dahlgren, Claes
    Department of Medical Microbiology, University of Göteborg, Göteborg, Sweden.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Particles binding β2-integrins mediate intracellular production of oxidative metabolites in human neutrophils independently of phagocytosis1999In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1452, no 2, p. 133-144Article in journal (Refereed)
    Abstract [en]

    Complement-opsonised particles are readily ingested by human neutrophils through a complement receptor-mediated process leading to phagolysosome fusion and production of oxidative metabolites. To investigate the complement receptor 3 (CR3)-associated signal system involved, cells were challenged with protein A-positive, heat-killed Staphylococcus aureus to which antibodies with specificity for the subunits of the β2-integrins, i.e. anti-CD11b (the α subunit of CR3) and anti-CD18 (the β subunit of CR3), were bound through their Fc moiety. Despite not being ingested by the neutrophils, the surface associated anti-CD18- and anti-CD11b-coated particles were able to activate the neutrophil NADPH-oxidase. Also anti-CD11a- (the α subunit of LFA-1) and to a lesser extent anti-CD11c- (the α subunit of CR4) coated particles were able to trigger the NADPH-oxidase. The NADPH-oxidase was activated without extracellular release of reactive oxygen species. The activity was inhibited by cytochalasin B, suggesting a necessary role for the cytoskeleton in the signalling pathway that activates the oxidase. We show that particle-mediated cross-linking of β2-integrins on the neutrophil surface initiates a signalling cascade, involving cytoskeletal rearrangements, leading to an activation of the NADPH-oxidase without phagosome formation or extracellular release of reactive oxygen species.

  • 56.
    Sjögren, Florence
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Dermatology.
    Ljunghusen, O
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Baas, A
    Coble, Britt-Inger
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Dermatology. Östergötlands Läns Landsting, Centre for Medicine, Department of Dermatology and Venerology in Östergötland.
    Stendahl, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Expression and function of beta-2 integrein CD11B/CD18 on leukocytes from patients with psoriasis. 1999In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 79, p. 105-110Article in journal (Refereed)
  • 57.
    Sjögren, Florence
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Dermatology.
    Stendahl, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Ljunghusen, Olof
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    The influence of retinoic acid and retinoic acid derivatives on Beta2 integrins and L-selectin expression in HL-60 cells in vitro2000In: Inflammation, ISSN 0360-3997, E-ISSN 1573-2576, Vol. 24, no 1, p. 21-32Article in journal (Refereed)
    Abstract [en]

    A decreased expression of the ▀2-integrin CD11b molecules on peripheral neutrophils from patients with pustular psoriasis occurred during treatment with retinoid compounds. Since this effect could not be mimicked in vitro with isolated peripheral neutrophils, the effect of retinoid compounds on cell differentiation was investigated. The promyelocytic cell line, HL60, was used to study what effect different retinoid compounds had on the cell surface expression of CD11b and L-selectin (CD62L) molecules, complement- mediated phagocytosis, adhesion and the oxidative burst. Retinoid- differentiated cells showed a significantly lower expression of CD11b and CD62L, and a decreased phagocytosis and oxidative burst compared to DMSO- differentiated HL60 cells or peripheral blood neutrophils. The diminished expression of ▀2-integrins or L-selectin did not affect their adhesion to non-activated or lipopolysaccharide-activated endothelial cells in vitro but may however affect adhesion to vascular endothelium under shear forces during blood flow. These results suggest that retinoid treatment could affect several early steps in the inflammatory process.

  • 58.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stimulation of macrophage innate immunity to prevent human mycobacterial disease in INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, vol 16, issue , pp E60-E602012In: INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, Elsevier , 2012, Vol. 16, p. E60-E60Conference paper (Refereed)
    Abstract [en]

    n/a

  • 59.
    Stendahl, Olle
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Krause, Karl-Heins
    Division of Infectious Diseases, Hôpital Cantonal Universitaire, Switzerland.
    Krischer, Joachim
    Department of Morphology, Centre Medical Universitaire, Switzerland.
    Jerström, Petra
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Theler, Jean-Marc
    Clinical Biochemistry, Centre Medical Universitaire, Switzerland.
    Clark, Rober A.
    Department of Medicine, VA Medical Center and University of Iowa, USA.
    Carpentier, Jean-Louis
    Department of Morphology, Centre Medical Universitaire, Switzerland.
    Lew, Daniel P.
    Division of Infectious Diseases, Hôpital Cantonal Universitaire, Switzerland.
    Redistribution of intracellular Ca2+ stores during phagocytosis in human neutrophils1994In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 265, no 5177, p. 1439-1441Article in journal (Refereed)
    Abstract [en]

    Subcellular gradients of cytosolic free Ca2+ concentration, [Ca2+]i, are thought to be critical for the localization of functional responses within a cell. A potential but previously unexplored mechanism for the generation of gradients of [Ca2+]i is the accumulation of Ca2+ stores at the site of Ca2+ action. The distribution of the Ca2+ store markers Ca(2+)-dependent adenosine triphosphatase and calreticulin was investigated in resting and phagocytosing human neutrophils. Both proteins showed an evenly distributed fine granular pattern in nonphagocytosing cells, but became markedly concentrated in the filamentous actin-rich cytoplasmic area around the ingested particle during phagocytosis. This redistribution began at early stages of phagocytosis and did not depend on an increase in [Ca2+]i. Thus, accumulation of Ca2+ stores in a restricted area of the cell may contribute to the generation of localized increases in [Ca2+]i.

  • 60.
    Welin, Amanda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Eklund, Daniel
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Human Macrophages Infected with a High Burden of ESAT-6-Expressing M. tuberculosis Undergo Caspase-1-and Cathepsin B-Independent Necrosis2011In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 5Article in journal (Refereed)
    Abstract [en]

    Mycobacterium tuberculosis (Mtb) infects lung macrophages, which instead of killing the pathogen can be manipulated by the bacilli, creating an environment suitable for intracellular replication and spread to adjacent cells. The role of host cell death during Mtb infection is debated because the bacilli have been shown to be both anti-apoptotic, keeping the host cell alive to avoid the antimicrobial effects of apoptosis, and pro-necrotic, killing the host macrophage to allow infection of neighboring cells. Since mycobacteria activate the NLRP3 inflammasome in macrophages, we investigated whether Mtb could induce one of the recently described inflammasome-linked cell death modes pyroptosis and pyronecrosis. These are mediated through caspase-1 and cathepsin-B, respectively. Human monocyte-derived macrophages were infected with virulent (H37Rv) Mtb at a multiplicity of infection (MOI) of 1 or 10. The higher MOI resulted in strongly enhanced release of IL-1 beta, while a low MOI gave no IL-1 beta response. The infected macrophages were collected and cell viability in terms of the integrity of DNA, mitochondria and the plasma membrane was determined. We found that infection with H37Rv at MOI 10, but not MOI 1, over two days led to extensive DNA fragmentation, loss of mitochondrial membrane potential, loss of plasma membrane integrity, and HMGB1 release. Although we observed plasma membrane permeabilization and IL-1 beta release from infected cells, the cell death induced by Mtb was not dependent on caspase-1 or cathepsin B. It was, however, dependent on mycobacterial expression of ESAT-6. We conclude that as virulent Mtb reaches a threshold number of bacilli inside the human macrophage, ESAT-6-dependent necrosis occurs, activating caspase-1 in the process.

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  • 61.
    Welin, Amanda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Human macrophages infected with virulent Mycobacterium tuberculosis undergo ESAT-6-dependent necrosis, but not pyroptosis or pyronecrosisManuscript (preprint) (Other academic)
    Abstract [en]

    Mycobacterium tuberculosis (Mtb) infects lung macrophages, which instead of killing the pathogen can be manipulated by the bacilli, creating an environment suitable for intracellular replication and spread to adjacent cells. The role of host cell death during Mtb infection is debated because the bacilli have been shown to be both anti-apoptotic, keeping the host cell alive to avoid the antimicrobial effects of apoptosis, and pro-necrotic, killing the host macrophage to allow infection of neighboring cells. Since mycobacteria are able to activate the NLRP3 inflammasome, we investigated whether Mtb could induce one of the recently described inflammasome-linked cell death modes pyroptosis and pyronecrosis, in human monocyte-derived macrophages. Cells were infected with virulent (H37Rv) Mtb at a multiplicity of infection (MOI) of 1 or 10. The higher MOI resulted in strongly enhanced release of IL-1β, while a low MOI gave no IL-1β response. The infected macrophages were collected and cell viability in terms of the integrity of DNA, mitochondria and the plasma membrane was determined. We found that infection with H37Rv at MOI 10, but not MOI 1, over two days led to extensive DNA fragmentation, loss of mitochondrial membrane potential and loss of plasma membrane integrity. Although we observed plasma membrane permeabilization and IL-1 β release from infected cells, the cell death induced by Mtb was not pyroptosis or pyronecrosis, as it was independent of caspase-1 and cathepsin B. Instead, we conclude that as virulent Mtb reaches a threshold number of bacilli inside the macrophage, ESAT-6-dependent necrosis occurs, activating caspase-1 in the process.

  • 62.
    Welin, Amanda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Raffetseder, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Importance of phagosomal functionality for growth restriction of Mycobacterium tuberculosis in primary human macrophages2011In: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 3, no 5, p. 508-518Article in journal (Refereed)
    Abstract [en]

    The best characterized survival mechanism of Mycobacterium tuberculosis inside the macrophage is the inhibition of phagosomal maturation. Phagosomal maturation involves several steps including fusion with lysosomes and acidification. However, it has not been elucidated which components of phagosomal maturation correlate with growth restriction of virulent mycobacteria in human macrophages, and we aimed to study this. We infected human monocyte-derived macrophages with M. tuberculosis and assessed bacterial replication, translocation of CD63 to the phagosome, and phagosomal acidification. We found that unstimulated macrophages were able to control infection with M. tuberculosis upon inoculation at a low, but not high, multiplicity of infection (MOI). H37Rv and H37Ra infection, at both high and low MOI, led to equally ineffective translocation of CD63 to the phagosome. This was true despite the impaired growth ability of H37Rv at the low MOI and of H37Ra even at the high MOI, indicating that inhibition of CD63 translocation was not sufficient for growth to occur. On the other hand, acidification of mycobacterial phagosomes was more efficient at a low MOI with both mycobacterial strains, consistent with a role for phagosomal acidification in restricting M. tuberculosis growth. Inhibition of the vacuolar H+-ATPase as well as of cathepsin D led to enhanced mycobacterial replication inside the macrophage. We conclude that acidification and related functional aspects of the mature phagosome are important factors for restriction of M. tuberculosis replication in human macrophages.

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  • 63.
    Welin, Amanda
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Winberg Tinnerfelt, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Abdalla, Hana
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Särndahl Lindblom, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Rasmusson, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Incorporation of Mycobacterium tuberculosis lipoarabinomannan into macrophage membrane rafts is a prerequisite for the phagosomal maturation block.2008In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 76, no 7, p. 2882-2887Article in journal (Refereed)
    Abstract [en]

    Lipoarabinomannan (LAM) is one of the key virulence factors for Mycobacterium tuberculosis, the etiological agent of tuberculosis. During uptake of mycobacteria, LAM interacts with the cell membrane of the host macrophage and can be detected throughout the cell upon infection. LAM can inhibit phagosomal maturation as well as induce a proinflammatory response in bystander cells. The aim of this study was to investigate how LAM exerts its action on human macrophages. We show that LAM is incorporated into membrane rafts of the macrophage cell membrane via its glycosylphosphatidylinositol anchor and that incorporation of mannose-capped LAM from M. tuberculosis results in reduced phagosomal maturation. This is dependent on successful insertion of the glycosylphosphatidylinositol anchor. LAM does not, however, induce the phagosomal maturation block through activation of p38 mitogen-activated protein kinase, contradicting some previous suggestions.

  • 64.
    Wilsson, Åsa
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Lundqvist, Helen
    Department of Medical Microbiology and Immunology, University of Göteborg.
    Gustafsson, Mikael
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Killing of phagocytosed Staphylococcus aureus by human neutrophils requires intracellular free calcium1996In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 59, no 6, p. 902-907Article in journal (Refereed)
    Abstract [en]

    The mobilization of intracellular calcium plays an important role in regulating neutrophil activation. With this in mind we investigated the effect of intra- and extracellular calcium on the ability of human neutrophils to kill complement-opsonized Staphylococcus aureus. We found that a rise in intracellular calcium is necessary for efficient killing of phagocytosed S. aureus. In the presence of extracellular calcium, killing of ingested bacteria in calcium-buffered neutrophils compared with normal cells was slightly reduced. Calcium buffering had no effect on phagocytic uptake by the neutrophils, but did decrease the generation of toxic oxygen metabolites, measured as chemiluminescence (CL). In nondepleted and calcium-depleted cells, removal of extracellular calcium did not affect ingestion but did cause a marked decrease in the ability to kill the bacteria. In parallel, the CL response was substantially reduced or completely blocked. These data show that calcium is not a prerequisite for phagocytosis of S. aureus by human neutrophils, but does play a vital role in the post-ingestion killing of the bacteria by regulating the generation of toxic oxygen metabolites.

  • 65.
    Wilsson, Åsa
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Majeed, Meytham
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Calcium requirements for vitronectin-mediated phagocytosis of Staphylococcus aureus by human neutrophilsManuscript (preprint) (Other academic)
    Abstract [en]

    In this paper we have shown that the intracellular free calcium concentration ([Ca2+]i) in human neutrophils regulates phagocytosis of Staphylococcus aureus adherent to vitronectin-coated surfaces. When neutrophils were allowed to phagocytose bacteria bound to vitronectin- or albumin-coated surfaces in tbe presence of Ca2+, there were no obvious differences in the phagocytic activity. Ca2+-depleted neut:ropbils showed a reduced phagocytic activity on vitronectin-coated surfaces. However, the phagocytosis on albumin-coated surfaces was unaffected. Adding extracellularly Ca2+ restored the reduced phagocytic activity in Ca2+-depleted neutrophils on vitronectincoated surfaces. Similarly, using a GRGDSP-peptide to block tbe RGDmediated integrin attachment of tbe neutrophils to vitronectin restored tbe reduced phagocytic activity in Ca2+-depleted cells. Studying phagocytosis in non-migrating neutrophils adherent to vitronectin showed that ingestion of S. aureus occurred independently of Ca2+. This indicate that Ca2+ regulate the phagocytic activity of neutrophils on vitronectin-coated surfaces by regulating integrin-dependent cell directed motility.

  • 66.
    Wilsson, Åsa
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Majeed, Meytham
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Enhancement of chemoattractant-induced oxidative activation during phagocytosis of Staphylococcus aureus by human neutrophilsManuscript (preprint) (Other academic)
    Abstract [en]

    Several studies have shown that the production of oxygen radicals in human neutrophils can be influenced by prior exposure to different priming agents, but the mechanism underlying priming is not fully understood. The present study shows that under reduced Ca2+-conditions, phagocytosis of viable, but not heat-killed S. aureus can prepare Ca2+-depleted neutrophils for an increased oxidative activation when stimulated with fMLP in the presence of Ca2+. This enhancement of the produced oxygen radicals, induced by viable S. aureus, was not due to differences in phagocytic uptake between viable or heat-killed bacteria by the neutrophils. We could neither detect any difference in the upregulation of chemoattractant receptors such as the fMLP receptor or complement receptor 3 (CR3) to the neutrophil cell surface. Phagocytosis of viable S. aureus by Ca2+-depleted neutrophils under reduced Ca2+-conditions, induced tyrosine phosphorylation of two proteins identified as phospholipase Cγ2 (PLCγ2) and Syk. Pretreatment of neutrophils with U-73122 or piceatannol, to selectively inhibit PLC and Syk, respectively, resulted in a marked suppression of the oxidative response in primed neutrophils. In addition, PP1, a drug known to selectively inhibit Srcfamily protein kinases inhibited the oxidative response in primedneutrophils. Moreover, bacterial uptake activated the Src- family protein kinase Lyn, which was inhibited by PPl. Phagocytosis of viable or heatkilled S. aureus did not show any difference in activation of p38 mitogenactivated protein kinase (MAPK) and inhibition of this kinase by SB203580 did not suppress the fMLP-induced oxidative activation inprimed neutrophils. The findings demonstrate that both priming and the induction of tyrosine phosphorylation of PLCγ2, Syk and Lyn are Ca2+-independent events, thus indicating that the phosphorylation of these intracellular targets plays a central role during the neutrophil priming by S. aureus.

  • 67.
    Ydrenius, Liselotte
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Majeed, Meytham
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    J Rasmusson, Birgitta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Stendahl, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Särndahl, Eva
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Activation of cAMP-dependent protein kinase is necessary for actin rearrangements in human neutrophils during phagocytosis2000In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 67, no 4, p. 520-528Article in journal (Refereed)
    Abstract [en]

    We have investigated the role of cAMP and cAMP-dependent protein kinase (cAPK) in neutrophil phagocytosis. Inhibition of cAPK with H-89 reduced complement- and IgG-dependent phagocytosis to 83 and 46%, respectively. Fluorescence intensity measurements of phalloidin-stained actin in neutrophils showed a reduced amount of filamentous actin (F-actin) in pseudopods and around the phagosome in cells treated with H-89 or cAMP-elevating agents (forskolin and rolipram). The amount of phosphotyrosine-containing proteins was also reduced in pseudopods and around the phagosome. Taken together, the data show that cAMP/cAPK regulates F-actin reorganization during receptor-mediated phagocytosis, particularly triggered by IgG-FcR interaction. Our results support the hypothesis that active subcortical reorganization of F-actin is a prerequisite for FcR-mediated phagocytosis, but is less important during CR3-mediated ingestion.

  • 68.
    Zheng, Limin
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Forsberg, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine.
    Stendahl, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Invasive Salmonella typhimurium induces apoptosis in human U937 cells by activating Rho GTPases2000In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 11, p. 1527-Conference paper (Other academic)
  • 69.
    Zheng, Limin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    He, Min
    Department of Biochemistry, College of Life Sciences, Sun Yatsen (Zhongshan) University, Guangzhou, China.
    Long, Min
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Pathogen-Induced Apoptotic Neutrophils Express Heat Shock Proteins and Elicit Activation of Human Macrophages2004In: Journal of immunology, ISSN 0022-1767, Vol. 173, no 10, p. 6319-6326Article in journal (Refereed)
    Abstract [en]

    Ingestion of aged or irradiated apoptotic neutrophils actively suppresses stimulation of macrophages (MΦ). Many bacterial pathogens can also provoke apoptosis in neutrophils, but little is known about how such apoptotic cells influence MΦ activation. We found that neutrophils undergoing apoptosis induced by UV irradiation, Escherichia coli, or Staphylococcus aureus could either stimulate or inhibit MΦ activation. In contrast to MΦ that had ingested irradiated apoptotic neutrophils, MΦ that had phagocytosed bacteria-induced apoptotic neutrophils exhibited markedly increased production of the proinflammatory cytokine TNF-α, but not the anti-inflammatory cytokine TGF-β. Moreover, ingestion of bacteria, but not UV-induced apoptotic neutrophils, caused increased expression of FcγRI on MΦ, and this effect was not provoked directly by bacteria associated with the apoptotic neutrophils. Instead, we found that a link between pathogen-induced apoptotic neutrophils and up-regulation of the heat shock proteins HSP60 and HSP70, and we also observed that recombinant HSP60 and HSP70 potentiated LPS-stimulated production of TNF-α in MΦ. The opposing macrophage responses to neutrophils undergoing apoptosis induced in different ways may represent a novel mechanism that regulates the extent of the immune response to invading microbes in two steps: first by aiding the functions of MΦ at an early stage of infection, and subsequently by deactivating those cells through removal of uninfected apoptotic neutrophils. HSP induction in neutrophils may provide the danger signals required to generate a more effective macrophage response.

  • 70.
    Zimmerli, Stefan
    et al.
    Division of Infectious Diseases and The Rosalind Russell Arthritis Research Laboratory, San Francisco General Hospital, University of California at San Francisco, San Francisco, California, USA.
    Majeed, Meytham
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Gustafsson, Mikael
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Stendahl, Olle
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Sanan, David A.
    Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
    Ernst, Joel D.
    Division of Infectious Diseases and The Rosalind Russell Arthritis Research Laboratory, San Francisco General Hospital, University of California at San Francisco, San Francisco, California, USA.
    Phagosome-Lysosome Fusion Is a Calcium-independent Event in Macrophages1996In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 132, no 1-2, p. 49-61Article in journal (Refereed)
    Abstract [en]

    Phagosome-lysosome membrane fusion is a highly regulated event that is essential for intracellular killing of microorganisms, Functionally, it represents a form of polarized regulated secretion, which is classically dependent on increases in intracellular ionized calcium ([Ca2+](i)). Indeed, increases in [Ca2+](i) are essential for phagosome-granule (lysosome) fusion in neutrophils and for lysosomal fusion events that mediate host cell invasion by Trypanosoma cruzi trypomastigotes, Since several intracellular pathogens survive in macrophage phagosomes that do not fuse with lysosomes, we examined the regulation of phagosome-lysosome fusion in macrophages. Macrophages (MO) were treated with 12.5 mu M bis-(2-amino-S-methylphenoxy) ethane-N,N,N',N',-tetraacetic acid tetraacetoxymethyl ester (MAPT/AM), a cell-permeant calcium chelator which reduced resting cytoplasmic [Ca2+]; from 80 nM to less than or equal to 20 nM and completely blocked increases in [Ca2+](i) in response to multiple stimuli, even in the presence of extracellular calcium, Subsequently, MO phagocytosed serum-opsonized zymosan, staphylococci, or Mycobacterium bovis, Microbes were enumerated by 4',6-diamidino-2-phenylindole, dihydrochloride (DAPI) staining, and phagosome-lysosome fusion was scored using both lysosome-associated membrane protein (LAMP-1) as a membrane marker and rhodamine dextran as a content marker for lysosomes, Confirmation of phagosomelysosome fusion by electron microscopy validated the fluorescence microscopy findings, We found that phagosome-lysosome fusion in MO occurs normally at very low [Ca2+](i) (less than or equal to 20 nM), Kinetic analysis showed that in MO none of the steps leading from particle binding to eventual phagosome-lysosome fusion are regulated by [Ca2+](i) in a rate-limiting way. Furthermore, confocal microscopy revealed no difference in the intensity of LAMP-1 immunofluorescence in phagolysosome membranes in calcium-buffered vs, control macrophages, We conclude that neither membrane recognition nor fusion events in the phagosomal pathway in macrophages are dependent on or regulated by calcium.

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