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  • Xiang, Richard F  (9)
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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: 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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  • 4
    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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  • 5
    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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  • 6
    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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  • 7
    Language: English
    In: Nat Commun, 2018, Vol.9(1), pp.751-751
    Description: Natural killer (NK) cells use the activating receptor NKp30 as a microbial pattern-recognition receptor to recognize, activate cytolytic pathways, and directly kill the fungi Cryptococcus neoformans and Candida albicans. However, the fungal pathogen-associated molecular pattern (PAMP) that triggers NKp30-mediated killing remains to be identified. Here we show that β-1,3-glucan, a component of the fungal cell wall, binds to NKp30. We further demonstrate that β-1,3-glucan stimulates granule convergence and polarization, as shown by live cell imaging. Through Src Family Kinase signaling, β-1,3-glucan increases expression and clustering of NKp30 at the microbial and NK cell synapse to induce perforin release for fungal cytotoxicity. Rather than blocking the interaction between fungi and NK cells, soluble β-1,3-glucan enhances fungal killing and restores defective cryptococcal killing by NK cells from HIV-positive individuals, implicating β-1,3-glucan to be both an activating ligand and a soluble PAMP that shapes NK cell host immunity.
    Keywords: Article;
    ISSN: 2041-1723
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  • 8
    In: International Immunology, 2019, Vol. 31(6), pp.385-396
    Description: Burkholderia cepacia complex (Bcc), which includes B. cenocepacia and B. multivorans , pose a life-threatening risk to patients with cystic fibrosis. Eradication of Bcc is difficult due to the high level of intrinsic resistance to antibiotics, and failure of many innate immune cells to control the infection. Because of the pathogenesis of Bcc infections, we wondered if a novel mechanism of microbial host defense involving direct antibacterial activity by natural killer (NK) cells might play a role in the control of Bcc. We demonstrate that NK cells bound Burkholderia , resulting in Src family kinase activation as measured by protein tyrosine phosphorylation, granule release of effector proteins such as perforin and contact-dependent killing of the bacteria. These studies provide a means by which NK cells could play a role in host defense against Bcc infection. NK cells kill Burkholderia species
    Keywords: Bacterial Infection ; Cytolytic Granules ; Nk Cell Contact - Dependent Killing ; Nk Cell Cytotoxicity ; Nk Cell Immunity
    ISSN: 09538178
    E-ISSN: 1460-2377
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  • 9
    In: Journal of Leukocyte Biology, June 2019, Vol.105(6), pp.1285-1296
    Description: It is now evident that NK cells kill bacteria, fungi, and parasites in addition to tumor and virus‐infected cells. In addition to a number of recent publications that have identified the receptors and ligands, and mechanisms of cytotoxicity, new insights are reflected in the reports from researchers all over the world at the 17th Meeting of the Society for Natural Immunity held in San Antonio, TX, USA from May 28 through June 1, 2018. We will provide an overview of the field and discuss how the presentations at the meeting might shape our knowledge and future directions in the field. Mechanisms of microbial killing by NK cells is rapidly providing novel insights in host defense as well as informing strategies for tumor cytotoxicity.
    Keywords: Nk Cells ; Microbial Killing ; Nk Activating Receptors ; Signal Transduction ; Granule Trafficking
    ISSN: 0741-5400
    E-ISSN: 1938-3673
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