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  • 1
    Online-Ressource
    Online-Ressource
    The Reduced Bactericidal Function of Complement C5-Deficient Murine Macrophages Is Associated with Defects in the Synthesis and Delivery of Reactive Oxygen Radicals to Mycobacterial Phagosomes
    The American Association of Immunologists ; 2006
    In:  The Journal of Immunology Vol. 177, No. 7 ( 2006-10-01), p. 4688-4698
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 177, No. 7 ( 2006-10-01), p. 4688-4698
    Kurzfassung: Complement C5-deficient (C5−/−) macrophages derived from B.10 congenic mice were found to be defective in killing intracellular Mycobacterium tuberculosis (MTB). They were bacteriostatic after activation with IFN-γ alone but bactericidal in the combined presence of IFN-γ and C5-derived C5a anaphylatoxin that was deficient among these macrophages. Reduced killing correlated with a decreased production of reactive oxygen species (ROS) in the C5−/− macrophages measured using fluorescent probes. Furthermore, a lack of colocalization of p47phox protein of the NADPH oxidase (phox) complex with GFP-expressing MTB (gfpMTB) indicated a defective assembly of the phox complex on phagosomes. Reconstitution with C5a, a known ROS activator, enhanced the assembly of phox complex on the phagosomes as well as the production of ROS that inhibited the growth of MTB. Protein kinase C (PKC) isoforms are involved in the phosphorylation and translocation of p47phox onto bacterial phagosomes. Western blot analysis demonstrated a defective phosphorylation of PKC (α, β, δ) and PKC-ζ in the cytosol of C5−/− macrophages compared with C5 intact (C5+/+) macrophages. Furthermore, in situ fluorescent labeling of phagosomes indicated that PKC-β and PKC-ζ were the isoforms that are not phosphorylated in C5−/− macrophages. Because Fc receptor-mediated phox assembly was normal in both C5−/− and C5+/+ macrophages, the defect in phox assembly around MTB phagosomes was specific to C5 deficiency. Reduced bactericidal function of C5−/− macrophages thus appears to be due to a defective assembly and production of ROS that prevents effective killing of intracellular MTB.
    Materialart: Online-Ressource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.177.7.4688
    RVK:
    XA 54100
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: The American Association of Immunologists
    Publikationsdatum: 2006
    ZDB Id: 1475085-5
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 2
    Online-Ressource
    Online-Ressource
    Processing and Presentation of a Mycobacterial Antigen 85B Epitope by Murine Macrophages Is Dependent on the Phagosomal Acquisition of Vacuolar Proton ATPase and In Situ Activation of Cathepsin D
    The American Association of Immunologists ; 2006
    In:  The Journal of Immunology Vol. 177, No. 5 ( 2006-09-01), p. 3250-3259
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 177, No. 5 ( 2006-09-01), p. 3250-3259
    Kurzfassung: Mycobacterium tuberculosis (strain H37Rv) and bacillus Calmette-Guérin (BCG) vaccine inhibit phagosome maturation in macrophages and their effect on processing, and presentation of a secreted Ag85 complex B protein, Ag85B, by mouse macrophages was analyzed. Macrophages were infected with GFP-expressing mycobacterial strains and analyzed for in situ localization of vacuolar proton ATPase (v-ATPase) and cathepsin D (Cat D) using Western blot analysis and immunofluorescence. H37Rv and BCG phagosomes excluded the v-ATPase and maintained neutral pH while the attenuated H37Ra strain acquired v-ATPase and acidified. Mycobacterial phagosomes acquired Cat D, although strains BCG and H37Rv phagosomes contained the inactive 46-kDa form, whereas H37Ra phagosomes had the active 30-kDa form. Infected macrophages were overlaid with a T cell hybridoma specific for an Ag85B epitope complexed with MHC class II. Coincident with active Cat D, H37Ra-infected macrophages presented the epitope to T cells inducing IL-2, whereas H37Rv- and BCG-infected macrophages were less efficient in IL-2 induction. Bafilomycin inhibited the induction of macrophage-induced IL-2 from T cells indicating that v-ATPase was essential for macrophage processing of Ag85B. Furthermore, the small interfering RNA interference of Cat D synthesis resulted in a marked decrease in the levels of macrophage-induced IL-2. Thus, a v-ATPase-dependent phagosomal activation of Cat D was required for the generation of an Ag85B epitope by macrophages. Reduced processing of Ag85B by H37Rv- and BCG-infected macrophages suggests that phagosome maturation arrest interferes with the efficient processing of Ags in macrophages. Because Ag85B is immunodominant, this state may lead to a decreased ability of the wild-type as well as the BCG vaccine to induce protective immunity.
    Materialart: Online-Ressource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.177.5.3250
    RVK:
    XA 54100
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: The American Association of Immunologists
    Publikationsdatum: 2006
    ZDB Id: 1475085-5
    Standort Signatur Einschränkungen Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Online-Ressource
  • 3
    Online-Ressource
    Online-Ressource
    Recombinant spore delivered M. tuberculosis antigens elicit immune response in mice
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 1_Supplement ( 2016-05-01), p. 145.4-145.4
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 145.4-145.4
    Kurzfassung: BCG, the vaccine against tuberculosis (TB), is one of the mandatory vaccines administered to infants in several parts of the world. However, BCG conferred immunity wanes when children reach adulthood. To develop booster vaccines, we engineered recombinant Bacillus subtilis spores to deliver Mycobacterium tuberculosis (Mtb) antigens. MTAG1 recombinant strain was designed to express a fusion protein of CotC-Ag85B-CFP10 on the spore coat, while MTAG2 and MTAG3 strains were designed to express Ag85B-CFP10 fusion protein in vegetative cells. The difference between MTAG2 and MTAG3 strains is that the latter expresses secreted listeriolysin (LLO) in addition to Ag85B-CFP10. Immunoblot analysis revealed that MTAG1 strain showed positive signals for Ag85B and CFP10 in the spore-coat and other strains in the vegetative cell extracts, indicating that antigens are expressed in these strains as expected. Splenocytes of mice immunized with recombinant spores, through intranasal route, displayed significantly higher antigen specific proliferation of IFN-γ producing cells compared to the splenocytes of control mice. Also, the culture fluids of splenocytes from recombinant spores immunized mice exhibited higher antigen specific release of Th1 cytokines than the culture fluids of splenocytes from control mice. These results indicate that antigens delivered via recombinant spores can be processed and presented to the immune cells. Additional in vivo studies may reveal whether these recombinant spores can be used to boost immunity in BCG vaccinated individuals.
    Materialart: Online-Ressource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.196.Supp.145.4
    RVK:
    XA 54100
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: The American Association of Immunologists
    Publikationsdatum: 2016
    ZDB Id: 1475085-5
    Standort Signatur Einschränkungen Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Online-Ressource
  • 4
    Online-Ressource
    Online-Ressource
    Genetic manipulation of BCG leads to altered presentation of CD4 and CD8 epitiopes from Antigen 85B by mouse dendritic cells. (78.22)
    The American Association of Immunologists ; 2009
    In:  The Journal of Immunology Vol. 182, No. 1_Supplement ( 2009-04-01), p. 78.22-78.22
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 182, No. 1_Supplement ( 2009-04-01), p. 78.22-78.22
    Kurzfassung: The partial efficacy of BCG vaccine has led to a search for more effective vaccines. The immuno-dominant antigen-85B (Ag85B) from BCG vaccine is processed in macrophages and dendritic cells (DCs) dependent upon the phagosomal pH and lysosomal delivery. However, BCG avoids lysosomal localization and its phagosomes are near neutral. We found that induction of autophagy enhanced the lysosomal delivery of BCG vaccine in DCs. This in turn increased the MHC-II dependent presentation of Ag85B which was detected using an Ag85B-specific T cell hybridoma. DCs also showed an enhanced presentation of Ag85B when infected with BCG that was engineered to over-express Ag85B. We found that over expressed (OE)-Ag85B triggered autophagy. Furthermore, Ag85B is secreted from BCG vaccine into the cytosol of DCs although BCG is inefficient in inducing CD8 T cells against Ag85B in mice. Since OE-Ag85B enhanced the MHC-II dependent presentation, we examined whether OE-Ag85B could also be routed through the proteasomal pathway. DCs were infected with BCG-OEAg85B and Ag85B presentation monitored with or without the blockade of proteasomes through lactacystin. Lactacystin enhanced the MHC-II dependent presentation of Ag85B suggesting that OE-Ag85B goes through the proteasome as well as lysosome during autophagy. Mice were then immunized with BCG-OEAg85B and the spleens were found to contain an increased number of CD8 T cells specific for an epitope of Ag85B detected using a pentamer-conjugate. We propose therefore that genetic manipulation of BCG may be used to alter the levels of CD4 and CD8 epitope presentation by DCs and alter vaccine efficacy.
    Materialart: Online-Ressource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.182.Supp.78.22
    RVK:
    XA 54100
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: The American Association of Immunologists
    Publikationsdatum: 2009
    ZDB Id: 1475085-5
    Standort Signatur Einschränkungen Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Online-Ressource
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