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Berlin Brandenburg

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  • 1
    Language: English
    In: Science (New York, N.Y.), 07 December 2018, Vol.362(6419), pp.1156-1160
    Description: Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters. In vitro, persister cells appear to be dormant. After uptake of species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood. In this work, we show that persisters arising during macrophage infection maintain a metabolically active state. Persisters reprogram macrophages by means of effectors secreted by the pathogenicity island 2 type 3 secretion system. These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization. Such reprogramming allowed nongrowing cells to survive for extended periods in their host. Persisters undermining host immune defenses might confer an advantage to the pathogen during relapse once antibiotic pressure is relieved.
    Keywords: Drug Resistance, Bacterial ; Host-Pathogen Interactions -- Immunology ; Macrophages -- Immunology ; Salmonella Infections -- Drug Therapy ; Salmonella Typhimurium -- Metabolism ; Type III Secretion Systems -- Metabolism
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 2
    Language: English
    In: Proc. Natl. Acad. Sci. USA, 20 November 2014, Vol.111((36) ; 09, 2014)
    Description: Neutrophils are indispensable for clearing infections with the prominent human pathogen Staphylococcus aureus. Here, we report that S. aureus secretes a family of proteins that potently inhibits the activity of neutrophil serine proteases (NSPs): neutrophil elastase (NE), proteinase 3, and cathepsin G. The NSPs, but not related serine proteases, are specifically blocked by the extracellular adherence protein (Eap) and the functionally orphan Eap homologs EapH1 and EapH2, with inhibitory-constant values in the low-nanomoiar range. Eap proteins are together essential for NSP inhibition by S. aureus in vitro and promote staphylococcal infection in vivo. The crystal structure of the EapH1/NE complex showed that Eap molecules constitute a unique class of noncovalent protease inhibitors that occlude the catalytic cleft of NSPs. These findings increase our insights into the complex pathogenesis of S. aureus infections and create opportunities to design novel treatment strategies for inflammatory conditions related to excessive NSP activity. immune evasion | bacteria | phagocytes www.pnas.org/cgi/doi/10.1073/pnas.1407616111
    Keywords: Staphylococcus Aureus -- Health Aspects ; Protease Inhibitors -- Health Aspects;
    ISSN: 00278424
    E-ISSN: 10916490
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  • 3
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 01 December 2014, Vol.193(11), pp.5506-14
    Description: The uptake of Ag-Ab immune complexes (IC) after the ligation of activating FcγR on dendritic cells (DC) leads to 100 times more efficient Ag presentation than the uptake of free Ags. FcγRs were reported to facilitate IC uptake and simultaneously induce cellular activation that drives DC maturation and mediates efficient T cell activation. Activating FcγRs elicit intracellular signaling via the ITAM domain of the associated FcRγ-chain. Studies with FcRγ-chain knockout (FcRγ(-/-)) mice reported FcRγ-chain ITAM signaling to be responsible for enhancing both IC uptake and DC maturation. However, FcRγ-chain is also required for surface expression of activating FcγRs, hampering the dissection of ITAM-dependent and independent FcγR functions in FcRγ(-/-) DCs. In this work, we studied the role of FcRγ-chain ITAM signaling using DCs from NOTAM mice that express normal surface levels of activating FcγR, but lack functional ITAM signaling. IC uptake by bone marrow-derived NOTAM DCs was reduced compared with wild-type DCs, but was not completely absent as in FcRγ(-/-) DCs. In NOTAM DCs, despite the uptake of ICs, both MHC class I and MHC class II Ag presentation was completely abrogated similar to FcRγ(-/-) DCs. Secretion of cytokines, upregulation of costimulatory molecules, and Ag degradation were abrogated in NOTAM DCs in response to FcγR ligation. Cross-presentation using splenic NOTAM DCs and prolonged incubation with OVA-IC was also abrogated. Interestingly, in this setup, proliferation of CD4(+) OT-II cells was induced by NOTAM DCs. We conclude that FcRγ-chain ITAM signaling facilitates IC uptake and is essentially required for cross-presentation, but not for MHC class II Ag presentation.
    Keywords: Cd4-Positive T-Lymphocytes -- Immunology ; Dendritic Cells -- Immunology ; Receptors, Igg -- Metabolism
    ISSN: 00221767
    E-ISSN: 1550-6606
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  • 4
    Language: English
    In: Current Opinion in Microbiology, February 2015, Vol.23, pp.42-48
    Description: Neutrophil serine proteases (NSPs) are critical for the effective functioning of neutrophils and greatly contribute to immune protection against bacterial infections. Thanks to their broad substrate specificity, these chymotrypsin-like proteases trigger multiple reactions that are detrimental to bacterial survival such as direct bacterial killing, generation of antimicrobial peptides, inactivation of bacterial virulence factors and formation of neutrophil extracellular traps. Recently, the importance of NSPs in antibacterial defenses has been further underscored by discoveries of unique bacterial evasion strategies to combat these proteases. Bacteria can indirectly disarm NSPs by protecting bacterial substrates against NSP cleavage, but also produce inhibitory molecules that potently block NSPs. Here we review recent insights in the functional contribution of NSPs in host protection against bacterial infections and the elegant strategies that bacteria use to counteract these responses.
    Keywords: Biology
    ISSN: 1369-5274
    E-ISSN: 1879-0364
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  • 5
    Language: English
    In: Current Opinion in Microbiology, 2015, Vol.23, p.42(7)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.mib.2014.11.002 Byline: Daphne AC Stapels, Brian V Geisbrecht, Suzan HM Rooijakkers Abstract: * Neutrophil serine proteases (NSPs) support bacterial clearance by neutrophils. * NSPs can kill bacteria, generate antimicrobial peptides or induce NET formation. * The anti-bacterial activities of NSPs are underlined by the discovery of bacterial inhibitors. * Gram-negative bacteria block chymotrypsin-like proteases like NSPs within the periplasm. * Staphylococcus aureus secretes a family of three highly specific NSP inhibitors. Author Affiliation: (1) Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands (2) Department of Biochemistry & Molecular Biophysics, Kansas State University, Manhattan, KS 66506, USA
    Keywords: Serine ; Proteases ; Antibacterial Agents
    ISSN: 1369-5274
    Source: Cengage Learning, Inc.
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  • 6
    In: Nature Microbiology, 2016, Vol.2
    Description: Intracellular bacterial pathogens can exhibit large heterogeneity in growth rate inside host cells, with major consequences for the infection outcome. If and how the host responds to this heterogeneity remains poorly understood. Here, we combined a fluorescent reporter of bacterial cell division with single-cell RNA-sequencing analysis to study the macrophage response to different intracellular states of the model pathogen Salmonella enterica serovar Typhimurium. The transcriptomes of individual infected macrophages revealed a spectrum of functional host response states to growing and non-growing bacteria. Intriguingly, macrophages harbouring non-growing Salmonella display hallmarks of the proinflammatory M1 polarization state and differ little from bystander cells, suggesting that non-growing bacteria evade recognition by intracellular immune receptors. By contrast, macrophages containing growing bacteria have turned into an anti-inflammatory, M2-like state, as if fast-growing intracellular Salmonella overcome host defence by reprogramming macrophage polarization. Additionally, our clustering approach reveals intermediate host functional states between these extremes. Altogether, our data suggest that gene expression variability in infected host cells shapes different cellular environments, some of which may favour a growth arrest of Salmonella facilitating immune evasion and the establishment of a long-term niche, while others allow Salmonella to escape intracellular antimicrobial activity and proliferate.
    Keywords: Biology;
    ISBN: 0003971049000
    E-ISSN: 2058-5276
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  • 7
    Language: English
    In: Immunobiology, November 2012, Vol.217(11), pp.1170-1170
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.imbio.2012.08.118 Byline: Daphne A.C. Stapels (1), Kasra X. Ramyar (2), Daniel Ricklin (3), Fin J.J. Milder (1)(4), Marcus Bischoff (5), Matthias Herrmann (5), Brian V. Geisbrecht (2), John D. Lambris (3), Maren von Kockritz-Blickwede (6), Kok P.M. van Kessel (1), Suzan H.M. Rooijakkers (1) Author Affiliation: (1) Medical Microbiology, UMC Utrecht, Utrecht, The Netherlands (2) Division of Cell Biology & Biophysics, University of Missouri-Kansas City, Kansas City, MO, USA (3) Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA (4) Crucell, Leiden, The Netherlands (5) Institute of Medical Microbiology and Hygiene, University of Saarland Hospital, Homburg/Saar, Germany (6) Department of Physiological Chemistry, University of Veterinary Medicine, Hannover, Germany
    Keywords: Biology
    ISSN: 0171-2985
    E-ISSN: 1878-3279
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  • 8
    Language: English
    In: Microbiology (Reading, England), July 2016, Vol.162(7), pp.1185-94
    Description: Staphylococcus aureus has developed many mechanisms to escape from human immune responses. To resist phagocytic clearance, S. aureus expresses a polysaccharide capsule, which effectively masks the bacterial surface and surface-associated proteins, such as opsonins, from recognition by phagocytic cells. Additionally, secretion of the extracellular fibrinogen binding protein (Efb) potently blocks phagocytic uptake of the pathogen. Efb creates a fibrinogen shield surrounding the bacteria by simultaneously binding complement C3b and fibrinogen at the bacterial surface. By means of neutrophil phagocytosis assays with fluorescently labelled encapsulated serotype 5 (CP5) and serotype 8 (CP8) strains we compare the immune-modulating function of these shielding mechanisms. The data indicate that, in highly encapsulated S. aureus strains, the polysaccharide capsule is able to prevent phagocytic uptake at plasma concentrations 〈10 %, but loses its protective ability at higher concentrations of plasma. Interestingly, Efb shows a strong inhibitory effect on both capsule-negative and encapsulated strains at all tested plasma concentrations. Furthermore, the results suggest that both shielding mechanisms can exist simultaneously and collaborate to provide optimal protection against phagocytosis at a broad range of plasma concentrations. As opsonizing antibodies will be shielded from recognition by either mechanism, incorporating both capsular polysaccharides and Efb in future vaccines could be of great importance.
    Keywords: Bacterial Capsules -- Metabolism ; Bacterial Proteins -- Metabolism ; Fibrinogen -- Metabolism ; Neutrophils -- Immunology ; Phagocytosis -- Immunology ; Polysaccharides, Bacterial -- Metabolism ; Staphylococcus Aureus -- Immunology
    ISSN: 13500872
    E-ISSN: 1465-2080
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  • 9
    In: Protein Science, February 2018, Vol.27(2), pp.509-522
    Description: Neutrophils contain high levels of chymotrypsin‐like serine proteases (NSPs) within their azurophilic granules that have a multitude of functions within the immune system. In response, the pathogen has evolved three potent inhibitors (Eap, EapH1, and EapH2) that protect the bacterium as well as several of its secreted virulence factors from the degradative action of NSPs. We previously showed that these so‐called EAP domain proteins represent a novel class of NSP inhibitors characterized by a non‐covalent inhibitory mechanism and a distinct target specificity profile. Based upon high levels of structural homology amongst the EAP proteins and the NSPs, as well as supporting biochemical data, we predicted that the inhibited complex would be similar for all EAP/NSP pairs. However, we present here evidence that EapH1 and EapH2 bind the canonical NSP, Neutrophil Elastase (NE), in distinct orientations. We discovered that alteration of EapH1 residues at the EapH1/NE interface caused a dramatic loss of affinity and inhibition of NE, while mutation of equivalent positions in EapH2 had no effect on NE binding or inhibition. Surprisingly, mutation of residues in an altogether different region of EapH2 severely impacted both the NE binding and inhibitory properties of EapH2. Even though EapH1 and EapH2 bind and inhibit NE and a second NSP, Cathepsin G, equally well, neither of these proteins interacts with the structurally related, but non‐proteolytic granule protein, azurocidin. These studies expand our understanding of EAP/NSP interactions and suggest that members of this immune evasion protein family are capable of diverse target recognition modes.
    Keywords: Neutrophil Serine Proteases ; Neutrophil Elastase ; S. Aureus ; Protease Inhibitor ; Protein Interactions
    ISSN: 0961-8368
    E-ISSN: 1469-896X
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  • 10
    Language: English
    In: Journal of Innate Immunity, October 2014, Vol.6(6), pp.860-868
    Description: Neutrophil extracellular traps (NETs) have been described as a fundamental innate immune defence mechanism. They consist of a nuclear DNA backbone associated with different antimicrobial peptides (AMPs) which are able to engulf and kill pathogens. The AMP LL-37, a member of the cathelicidin family, is highly present in NETs. However, the function of LL-37 within NETs is still unknown because it loses its antimicrobial activity when bound to DNA in the NETs. Using immunofluorescence microscopy, we demonstrate that NETs treated with LL-37 are distinctly more resistant to S. aureus nuclease degradation than nontreated NETs. Biochemical assays utilising a random LL-37-fragment library indicated that the blocking effect of LL-37 on nuclease activity is based on the cationic character of the AMP, which facilitates the binding to neutrophil DNA, thus protecting it from degradation by the nuclease. In good correlation to these data, the cationic AMPs human beta defensin-3 and human neutrophil peptide-1 showed similar protection of neutrophil-derived DNA against nuclease degradation. In conclusion, this study demonstrates a novel role of AMPs in host immune defence: beside its direct antimicrobial activity against various pathogens, cationic AMPs can stabilise neutrophil-derived DNA or NETs against bacterial nuclease degradation.
    Keywords: Research Article ; Antimicrobial Peptides ; Neutrophil Extracellular Traps ; Nucleases ; Cathelicidin ; Biology
    ISSN: 1662-811X
    E-ISSN: 1662-8128
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