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Berlin Brandenburg

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  • 1
    Language: English
    In: The Journal of biological chemistry, 25 March 2016, Vol.291(13), pp.6912-22
    Description: The activity of Rac in leukocytes is essential for immunity. However, its role in NK cell-mediated anti-microbial signaling remains unclear. In this study, we investigated the role of Rac in NK cell mediated anti-cryptococcal killing. We found thatCryptococcus neoformansindependently activates both Rac and SFK pathways in NK cells, and unlike in tumor killing,Cryptococcusinitiated a novel Rac → PI3K → Erk cytotoxicity cascade. Remarkably, Rac was not required for conjugate formation, despite its essential role in NK cytotoxicity againstC. neoformans Taken together, our data show that, unlike observations with tumor cells, NK cells use a novel Rac cytotoxicity pathway in conjunction with SFK, to killC. neoformans.
    Keywords: Cellular Signaling ; Cryptococcus ; Rac (Rac Gtpase) ; Src ; Adhesion ; Fungi ; Natural Killer Cells (Nk Cells) ; Phosphatidylinositide 3-Kinase (PI 3-Kinase) ; Cytotoxicity, Immunologic ; Class Ia Phosphatidylinositol 3-Kinase -- Immunology ; Cryptococcus Neoformans -- Physiology ; Killer Cells, Natural -- Immunology ; Rac Gtp-Binding Proteins -- Immunology ; Rac1 Gtp-Binding Protein -- Immunology ; Src-Family Kinases -- Immunology
    E-ISSN: 1083-351X
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  • 2
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 15 October 2018, Vol.201(8), pp.2369-2376
    Description: is a fungal pathogen that causes fatal meningitis and pneumonia. During host defense to , NK cells directly recognize and kill using cytolytic degranulation analogous to killing of tumor cells. This fungal killing requires independent activation of Src family kinase (SFK) and Rac1-mediated pathways. Recognition of requires the natural cytotoxicity receptor, NKp30; however, it is not known whether NKp30 activates both signal transduction pathways or whether a second receptor is involved in activation of one of the pathways. We used primary human NK cells and a human NK cell line and found that NKp30 activates SFK → PI3K but not Rac1 cytotoxic signaling, which led to a search for the receptor leading to Rac1 activation. We found that NK cells require integrin-linked kinase (ILK) to activate Rac1 for effective fungal killing. This observation led to our identification of β1 integrin as an essential anticryptococcal receptor. These findings demonstrate that multiple receptors, including β1 integrins and NKp30 and their proximal signaling pathways, are required for recognition of , which activates a central cytolytic antimicrobial pathway leading to fungal killing.
    Keywords: Cryptococcosis -- Immunology ; Cryptococcus Neoformans -- Physiology ; Integrin Beta1 -- Metabolism ; Killer Cells, Natural -- Immunology ; Rac1 Gtp-Binding Protein -- Metabolism
    ISSN: 00221767
    E-ISSN: 1550-6606
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  • 3
    Language: English
    In: Infection and immunity, October 2013, Vol.81(10), pp.3912-22
    Description: Natural killer (NK) cells directly recognize and kill fungi, such as the pathogenic fungus Cryptococcus neoformans, via cytolytic mechanisms. However, the precise signaling pathways governing this NK cell microbicidal activity and the implications for fungal recognition are still unknown. Previously, it was reported that NK cell anticryptococcal activity is mediated through a conserved phosphatidylinositol 3-kinase-extracellular signal-regulated kinase 1/2 (PI3K-ERK1/2) pathway. Using YT (a human NK-like cell line) and primary human NK cells, we sought to identify the upstream, receptor-proximal signaling elements that led to fungal cytolysis. We demonstrate that Src family kinases were activated in response to C. neoformans. Furthermore, pharmacologic inhibition with an Src kinase inhibitor blocked C. neoformans-induced downstream activation of PI3K and ERK1/2 and abrogated cryptococcal killing. At the same time, the inhibitor disrupted the polarization of perforin-containing granules toward the NK cell-cryptococcal synapse but had no effect on conjugate formation between the organism and the NK cell. Finally, small interfering RNA (siRNA) double (but not single) knockdown of two Src family kinases, Fyn and Lyn, blocked cryptococcal killing. Together these data demonstrate a mechanism whereby the Src family kinases, Fyn and Lyn, redundantly mediate anticryptococcal activity through the activation of PI3K and ERK1/2, which in turn facilitates killing by inducing the polarization of perforin-containing granules to the NK cell-cryptococcal synapse.
    Keywords: Cryptococcus Neoformans -- Physiology ; Killer Cells, Natural -- Metabolism ; Perforin -- Metabolism ; Proto-Oncogene Proteins C-Fyn -- Metabolism ; Src-Family Kinases -- Metabolism
    E-ISSN: 1098-5522
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  • 4
    In: Journal of Neurochemistry, March 2012, Vol.120(6), pp.851-852
    Description: Peer Reviewed
    Keywords: Chemistry ; Anatomy & Physiology;
    ISSN: 0022-3042
    E-ISSN: 1471-4159
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  • 5
    Language: English
    In: mBio, 01 August 2016, Vol.7(4), p.e00878-16
    Description: Cryptococcus neoformans is a pathogenic yeast and a leading cause of life-threatening meningitis in AIDS patients. Natural killer (NK) cells are important immune effector cells that directly recognize and kill C. neoformans via a perforin-dependent cytotoxic mechanism. We previously showed that NK cells from HIV-infected patients have aberrant anticryptococcal killing and that interleukin-12 (IL-12) restores the activity at least partially through restoration of NKp30. However, the mechanisms causing this defect or how IL-12 restores the function was unknown. By examining the sequential steps in NK cell killing of Cryptococcus, we found that NK cells from HIV-infected patients had defective binding of NK cells to C. neoformans. Moreover, those NK cells that bound to C. neoformans failed to polarize perforin-containing granules to the microbial synapse compared to healthy controls, suggesting that binding was insufficient to restore a defect in perforin polarization. We also identified lower expression of intracellular perforin and defective perforin release from NK cells of HIV-infected patients in response to C. neoformans. Importantly, treatment of NK cells from HIV-infected patients with IL-12 reversed the multiple defects in binding, granule polarization, perforin content, and perforin release and restored anticryptococcal activity. Thus, there are multiple defects in the cytolytic machinery of NK cells from HIV-infected patients, which cumulatively result in defective NK cell anticryptococcal activity, and each of these defects can be reversed with IL-12.
    Keywords: Biology
    E-ISSN: 2150-7511
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  • 6
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 01 February 2016, Vol.196(3), pp.1259-71
    Description: Cryptococcus gattii is an emerging fungal pathogen on the west coast of Canada and the United States that causes a potentially fatal infection in otherwise healthy individuals. In previous investigations of the mechanisms by which C. gattii might subvert cell-mediated immunity, we found that C. gattii failed to induce dendritic cell (DC) maturation, leading to defective T cell responses. However, the virulence factor and the mechanisms of evasion of DC maturation remain unknown. The cryptococcal polysaccharide capsule is a leading candidate because of its antiphagocytic properties. Consequently, we asked if the capsule of C. gattii was involved in evasion of DC maturation. We constructed an acapsular strain of C. gattii through CAP59 gene deletion by homologous integration. Encapsulated C. gattii failed to induce human monocyte-derived DC maturation and T cell proliferation, whereas the acapsular mutant induced both processes. Surprisingly, encapsulation impaired DC maturation independent of its effect on phagocytosis. Indeed, DC maturation required extracellular receptor signaling that was dependent on TNF-α and p38 MAPK, but not ERK activation, and the cryptococcal capsule blocked this extracellular recognition. Although the capsule impaired phagocytosis that led to pH-dependent serine-, threonine-, and cysteine-sensitive protease-dependent Ag processing, it was insufficient to impair T cell responses. In summary, C. gattii affects two independent processes, leading to DC maturation and Ag processing. The polysaccharide capsule masked extracellular detection and reduced phagocytosis that was required for DC maturation and Ag processing, respectively. However, the T cell response was fully restored by inducing DC maturation.
    Keywords: Antigen Presentation -- Immunology ; Cryptococcosis -- Immunology ; Cryptococcus Gattii -- Immunology ; Dendritic Cells -- Immunology ; Fungal Capsules -- Immunology ; Immune Evasion -- Immunology
    E-ISSN: 1550-6606
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 7
    Language: English
    In: Cell Host & Microbe, 16 October 2013, Vol.14(4), pp.387-397
    Description: Natural killer (NK) cells are a subset of immune effectors that directly bind and kill fungi via a perforin-dependent mechanism. The receptor mediating this activity and its potential role in disease remain unknown. Using an unbiased approach, we determined that NKp30 is responsible for recognition and killing of the fungal pathogens and NKp30 was required for NK cell-fungal conjugate formation, phosphatidylinositol 3-kinase (PI3K) signaling, and perforin release. Because fungal infections are a leading cause of death in AIDS patients, we examined NKp30 expression in HIV-infected patients. NK cells from these patients had diminished NKp30 expression, defective perforin release, and blunted microbicidal activity. Surprisingly, interleukin-12 (IL-12) restored NKp30 expression and fungal killing. Thus, the NKp30 receptor plays a critical role in NK cell antifungal cytotoxicity, and diminished expression of NKp30 is responsible for defective antifungal activity of NK cells from HIV-infected patients, which can be corrected with IL-12.
    Keywords: Biology
    ISSN: 1931-3128
    E-ISSN: 1934-6069
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  • 8
    Language: English
    In: Cell Reports, 11 September 2018, Vol.24(11), pp.3017-3032
    Description: is the most important cause of fungal meningitis in immunocompromised individuals. Host defense against involves direct killing by NK cells. That NK cells from HIV-infected patients fail to polarize perforin to the microbial synapse and kill led us to explore the mechanisms used to reposition and polarize the cytolytic granules to the synapse. Using live-cell imaging, we observed microtubule and granule movements in response to that revealed a kinesin-dependent event. Eg5-kinesin bound to perforin-containing granules and was required for association with the microtubules. Inhibition of Eg5-kinesin abrogated dynein-dependent granule convergence to the MTOC and granule and MTOC polarization to the synapse and suppressed NK cell killing of . In contrast, Eg5-kinesin was dispensable for tumor killing. This reveals an alternative mechanism of MTOC repositioning and granule polarization, not used in tumor cytotoxicity, in which Eg5-kinesin is required to initiate granule movement, leading to microbial killing. The mechanisms of cytolytic granules deployment and the events leading to selective use of perforin, and not granulysin, in NK-cell-mediated killing of are unknown. Ogbomo et al. demonstrate that Eg5-kinesin and dynein control these events. Eg5-kinesin activity is required to turn on dynein activity for directed cytotoxicity.
    Keywords: Eg5-Kinesin ; Dynein ; Nk Cell Cytotoxicity ; Granule Congregation ; Granule Convergence ; Microtubule Organizing Center Polarization ; Perforin ; Granulysin ; Biology
    ISSN: 2211-1247
    E-ISSN: 2211-1247
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  • 9
    Language: English
    In: Nature Communications, 01 February 2018, Vol.9(1), pp.1-13
    Description: Natural killer (NK) cells has been show to mediate fungi killing via the activating receptor NKp30, but the fungal target for NKp30 is still unclear. Here the authors show, using atomic force microscopy and live cell imaging, that β-1,3-glucan is expressed by Cryptococcus neoformans and Candida albicans and responsible for NKp30-mediated NK killing.
    Keywords: Biology
    E-ISSN: 2041-1723
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  • 10
    Language: English
    In: 2013, Vol.9(7), p.e1003439
    Description: Cryptococcus gattii and Cryptococcus neoformans are encapsulated yeasts that can produce a solid tumor-like mass or cryptococcoma. Analogous to malignant tumors, the microenvironment deep within a cryptococcoma is acidic, which presents unique challenges to host defense. Analogous to malignant cells, NK cells kill Cryptococcus . Thus, as in tumor defense, NK cells must kill yeast cells across a gradient from physiologic pH to less than 6 in the center of the cryptococcoma. As acidic pH inhibits anti-tumor activities of NK cells, we sought to determine if there was a similar reduction in the anticryptococcal activity of NK cells. Surprisingly, we found that both primary human NK cells and the human NK cell line, YT, have preserved or even enhanced killing of Cryptococcus in acidic, compared to physiological, pH. Studies to explore the mechanism of enhanced killing revealed that acidic pH does not increase the effector to target ratio, binding of cytolytic cells to Cryptococcus , or the active perforin content in effector cells. By contrast, perforin degranulation was greater at acidic pH, and increased degranulation was preceded by enhanced ERK1/2 phosphorylation, which is essential for killing. Moreover, using a replication defective ras1 knockout strain of Cryptococcus increased degranulation occurred during more rapid replication of the organisms. Finally, NK cells were found intimately associated with C. gattii within the cryptococcoma of a fatal infection. These results suggest that NK cells have amplified signaling, degranulation, and greater killing at low pH and when the organisms are replicating quickly, which would help maintain microbicidal host defense despite an acidic microenvironment. ; Immune responses that protect from infection must occur in a variety of unique and potentially hostile environments. Within these environments, acidosis causes profound affects on protective responses. Low pH can occur in focal tumor-like infections, such as in a cryptococcoma produced by the fungal pathogen . Similarly, low pH occurs in focal malignant tumors. It follows that and malignant cells can both be killed by NK cells, which provide an important mechanism of host defense. Thus, we asked whether low pH, which impairs tumor killing, might also affect NK cell killing of . Surprisingly, despite impaired tumor killing, NK cells possess enhanced killing of at low pH. The mechanism involved a gain in intracellular signal transduction that led to enhanced perforin degranulation. This led us to examine NK cells in persistent cryptococcoma of a fatal brain infection and lung. We found that NK cells associate with within the cryptococcoma, but perforin is reduced. These studies suggest NK cell cytotoxicity need not be impaired at low pH, and that enhanced signal transduction and degranulation at low pH might be used to enhance host defense.
    Keywords: Research Article ; Biology ; Medicine
    ISSN: 1553-7366
    E-ISSN: 1553-7374
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