Browsing by Subject "Host defense"

Now showing 1 - 4 of 4
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    Adaptive NK cells in people exposed to Plasmodium falciparum correlate with protection from malaria
    (Rockefeller University Press, 2019-04-12) Hart, Geoffrey T.; Tran, Tuan M.; Theorell, Jakob; Schlums, Heinrich; Arora, Gunjan; Rajagopalan, Sumati; Sangala, A. D. Jules; Welsh, Kerry J.; Traore, Boubacar; Pierce, Susan K.; Crompton, Peter D.; Bryceson, Yenan T.; Long, Eric O.; Medicine, School of Medicine
    How antibodies naturally acquired during Plasmodium falciparum infection provide clinical immunity to blood-stage malaria is unclear. We studied the function of natural killer (NK) cells in people living in a malaria-endemic region of Mali. Multi-parameter flow cytometry revealed a high proportion of adaptive NK cells, which are defined by the loss of transcription factor PLZF and Fc receptor γ-chain. Adaptive NK cells dominated antibody-dependent cellular cytotoxicity responses, and their frequency within total NK cells correlated with lower parasitemia and resistance to malaria. P. falciparum–infected RBCs induced NK cell degranulation after addition of plasma from malaria-resistant individuals. Malaria-susceptible subjects with the largest increase in PLZF-negative NK cells during the transmission season had improved odds of resistance during the subsequent season. Thus, antibody-dependent lysis of P. falciparum–infected RBCs by NK cells may be a mechanism of acquired immunity to malaria. Consideration of antibody-dependent NK cell responses to P. falciparum antigens is therefore warranted in the design of malaria vaccines.
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    DISTINCT LOCALIZATION OF NADPH OXIDASE FLAVOCYTOCHROME B IN RESTING AND INTERFERON GAMMA ACTIVATED MACROPHAGES
    (2009-06-22T19:52:25Z) Casbon, Amy Jo; Dinauer, Mary C; Kaplan, Mark H.; Bauer, Margaret E.; Pavalko, Fredrick M.
    Flavocytochrome b558, the catalytic core of the phagocytic NADPH oxidase, mediates the transfer of electrons from NADPH to molecular oxygen to generate superoxide for host defense. Flavocytochrome b is a membrane heterodimer consisting of a large subunit gp91phox (NOX2) and a smaller subunit, p22phox. Localization of flavocytochrome b to the phagosome is essential for microbial killing, yet the subcellular distribution of flavocytochrome b in macrophages and how it is incorporated into macrophage phagosomes is not well characterized. In neutrophils, flavocytochrome b localizes primarily to specific granules that are rapidly mobilized to the phagosome upon stimulation. In contrast to neutrophils, macrophages do not contain specific granules, and trafficking of membrane proteins to the phagosome is more dynamic, involving fission and fusion events with endosomal compartments. We hypothesized that in macrophages, flavocytochrome b localizes to both plasma membrane and endosomal compartments that deliver flavocytochrome b to the phagosome. We generated fluorescently tagged versions of both p22phox and gp91phox, and rigorously verified their functionality in Chinese Hamster Ovary cells. Localization of flavocytochrome b was then examined in both RAW 264.7 murine macrophages and primary murine bone marrow derived macrophages (BMDM) in the presence and absence of interferon gamma (IFNg). We found that in “resting” macrophages, flavocytochrome b localizes primarily to the Rab11-positive endosome recycling compartment that recycles to the plasma membrane. In addition, phagocytosis assays showed flavocytochrome b is incorporated into the phagocytic cup and colocalized with Rab11 at the base of the cup, suggesting Rab11-positive endosomes may be involved in trafficking of flavocytochrome b between intracellular membranes and forming or nascent phagosomes. However, in IFNg activated macrophages, flavocytochrome b was localized predominantly in the plasma membrane, with little present in endosomal compartments. This shift in flavocytochrome b distribution occurred following sustained exposure to IFNg and correlated with increased flavocytochrome b protein expression and increased extracellular production of superoxide. Taken together, our results suggest the IFNg-induced redistribution of flavocytochrome b may be important for enhancing the production of superoxide at the cell surface and may be a potential new mechanism by which IFNg enhances antimicrobial activity in macrophages.
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    In Staphylococcus aureus, the Particulate State of the Cell Envelope Is Required for the Efficient Induction of Host Defense Responses
    (American Society for Microbiology, 2019-11-18) Kim, ByungHyun; Jiang, TingTing; Bae, Jun-Hyun; Yun, Hye Su; Jang, Seong Han; Kim, Jung Hyun; Kim, Jae Deog; Hur, Jin-Hoe; Shibata, Kensuke; Kurokawa, Kenji; Jung, Yunjin; Peschel, Andreas; Bae, Taeok; Lee, Bok Luel; Microbiology and Immunology, School of Medicine
    Upon microbial infection, host immune cells recognize bacterial cell envelope components through cognate receptors. Although bacterial cell envelope components function as innate immune molecules, the role of the physical state of the bacterial cell envelope (i.e., particulate versus soluble) in host immune activation has not been clearly defined. Here, using two different forms of the staphylococcal cell envelope of Staphylococcus aureus RN4220 and USA300 LAC strains, we provide biochemical and immunological evidence that the particulate state is required for the effective activation of host innate immune responses. In a murine model of peritoneal infection, the particulate form of the staphylococcal cell envelope (PCE) induced the production of chemokine (C-X-C motif) ligand 1 (CXCL1) and CC chemokine ligand 2 (CCL2), the chemotactic cytokines for neutrophils and monocytes, respectively, resulting in a strong influx of the phagocytes into the peritoneal cavity. In contrast, compared with PCE, the soluble form of cell envelope (SCE), which was derived from PCE by treatment with cell wall-hydrolyzing enzymes, showed minimal activity. PCE also induced the secretion of calprotectin (myeloid-related protein 8/14 [MRP8/14] complex), a phagocyte-derived antimicrobial protein, into the peritoneal cavity at a much higher level than did SCE. The injected PCE particles were phagocytosed by the infiltrated neutrophils and monocytes and then delivered to mediastinal draining lymph nodes. More importantly, intraperitoneally (i.p.) injected PCE efficiently protected mice from S. aureus infection, which was abolished by the depletion of either monocytes/macrophages or neutrophils. This study demonstrated that the physical state of bacterial cells is a critical factor for efficient host immune activation and the protection of hosts from staphylococcal infections.
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    Too much of a good thing: How modulating LTB4 actions restore host defense in homeostasis or disease
    (Elsevier, 2017-10) Brandt, Stephanie L.; Serezani, C. Henrique; Microbiology and Immunology, School of Medicine
    The ability to regulate inflammatory pathways and host defense mechanisms is critical for maintaining homeostasis and responding to infections and tissue injury. While unbalanced inflammation is detrimental to the host; inadequate inflammation might not provide effective signals required to eliminate pathogens. On the other hand, aberrant inflammation could result in organ damage and impair host defense. The lipid mediator leukotriene B4 (LTB4) is a potent neutrophil chemoattractant and recently, its role as a dominant molecule that amplifies many arms of phagocyte antimicrobial effector function has been unveiled. However, excessive LTB4 production contributes to disease severity in chronic inflammatory diseases such as diabetes and arthritis, which could potentially be involved in poor host defense in these groups of patients. In this review we discuss the cellular and molecular programs elicited during LTB4 production and actions on innate immunity host defense mechanisms as well as potential therapeutic strategies to improve host defense.