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  • The American Association of Immunologists  (3)
  • 1
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 135.17-135.17
    Abstract: Cryptococcus neoformans is a common opportunistic pathogen that requires intact T cell-mediated immunity for protective host defenses. While Th1/Th17 responses contribute to the effective containment and elimination of C. neoformans, Th2 responses are non-protective and can worsen clearance outcomes. Previous studies showed that early tumor necrosis factor alpha (TNFα) signaling is required for optimal clearance, while its absence leads to immune dysregulation and persistent fungal infection. To determine mechanism(s) of early TNFα signaling in the generation of protective anti-cryptococcal immunity, we evaluated the contribution of TNFα to the priming of the innate immune system for optimal T-cell development. In CBA/J mice depleted of TNFα at the time of infection with C. neoformans, we evaluated DC accumulation, activation profile, and interaction frequencies with T cells in lung associated lymph nodes (LALN) in comparison with the infected control mice. We found that early TNFα depletion during pulmonary C. neoformans infection resulted in: 1) lack of pulmonary fungal clearance and enhanced dissemination; 2) decreased Th1/Th17 polarization and CD4+ T cell activation in the LALN; 3) diminished DC accumulation in the LALN; 4) decreased expression of classical activation DC signatures (co-stimulatory molecules CD40 and CD86), pro-Th1 and pro-Th17 cytokines (IL-12b, TNFα, IL-23a and IL-21); and 5) increased expression of the alternative activation DC signatures (Fizz and Gal3) and pro-Th2 cytokines (IL4 and IL-10). Thus, our data indicates early TNFα signaling promotes classical activation of DC in lung associated lymph nodes thereby priming development of protective immunity against cryptococcal infection.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    RVK:
    RVK:
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
    detail.hit.zdb_id: 1475085-5
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  • 2
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 9 ( 2017-05-01), p. 3548-3557
    Abstract: The scavenger receptor macrophage receptor with collagenous structure (MARCO) promotes protective innate immunity against bacterial and parasitic infections; however, its role in host immunity against fungal pathogens, including the major human opportunistic fungal pathogen Cryptococcus neoformans, remains unknown. Using a mouse model of C. neoformans infection, we demonstrated that MARCO deficiency leads to impaired fungal control during the afferent phase of cryptococcal infection. Diminished fungal containment in MARCO−/− mice was accompanied by impaired recruitment of Ly6Chigh monocytes and monocyte-derived dendritic cells (moDC) and lower moDC costimulatory maturation. The reduced recruitment and activation of mononuclear phagocytes in MARCO−/− mice was linked to diminished early expression of IFN-γ along with profound suppression of CCL2 and CCL7 chemokines, providing evidence for roles of MARCO in activation of the CCR2 axis during C. neoformans infection. Lastly, we found that MARCO was involved in C. neoformans phagocytosis by resident pulmonary macrophages and DC. We conclude that MARCO facilitates early interactions between C. neoformans and lung-resident cells and promotes the production of CCR2 ligands. In turn, this contributes to a more robust recruitment and activation of moDC that opposes rapid fungal expansion during the afferent phase of cryptococcal infection.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    RVK:
    RVK:
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 3
    Online Resource
    Online Resource
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 1_Supplement ( 2016-05-01), p. 135.18-135.18
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 135.18-135.18
    Abstract: Resistance to the opportunistic fungal pathogen Cryptococcus neoformans (Cn) is associated with development of Th1/Th17 immune bias while a Th2 immune response results in increased susceptibility. Macrophage Receptor with Collagenous Structure (MARCO) is important for recognition of some pathogens and subsequent activation and polarization of the immune responses by DC and macrophages, however, its role during Cn infection remains unknown. Here we found that in spite of diminished early (innate) control of Cn in the infected lungs, Cn-infected MARCO−/− mice showed improved fungal clearance during the adaptive phase (wk 5) compared to MARCO+/+ mice. MARCO−/− mice showed: 1) improved accumulation of exudate macrophages and CD11b+ DC and their improved activation phenotype (CD80+, CD86+ and MHCIIhigh); 2) increased intracellular IFN-γ and IL-17 production by pulmonary CD4+ and CD8+ T cells; 3) decreased IL-4, IL-5, IL-10 and increased IFN-γ and IL-17 production by splenocytes treated with Cn antigen; 5) diminished systemic level of IgE. Interestingly, in spite of improved clearance, MARCO−/− mice showed decreased frequency of lung resident CD44highCD62LlowCD69+ CD103+CD11a+CCR7− effector memory T cells. We conclude that while important for the innate control of Cn in the lungs, MARCO can be exploited by Cn to interfere with immune polarization leading to an altered, non-protective efferent immune bias, which outweighs potentially beneficial effects of MARCO.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    RVK:
    RVK:
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
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