2024-03-28T08:08:05Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/146282019-08-30T11:27:16Zcom_10033_620618col_10033_620621
2007-11-19T13:54:12Z
urn:hdl:10033/14628
Vaccination equally enables both genetically susceptible and resistant mice to control infection with group A streptococci.
Siegert, Jeannette
Sastalla, Inka
Chhatwal, Gursharan Singh
Medina, Eva
There is substantial evidence that host genetic factors are important in determining susceptibility to infection with group A streptococci (GAS). Several studies have revealed that, similarly to humans, a genetic component may be important in determining susceptibility to GAS infection in mice. Thus, C3H/HeN mice are much more susceptible to streptococcal infection than BALB/c mice. We have determined here whether vaccination makes genetically susceptible mice as capable as genetically resistant mice to control GAS infection. Resistant BALB/c and susceptible C3H/HeN mice were immunized either systemically with heat-killed GAS or through the mucosal route with an M protein-based subunit vaccine, and challenged with live bacteria. Vaccination elicited in both mouse strains similar levels of bactericidal anti-GAS IgG antibodies and also antigen-specific mucosal IgA. Vaccination provided mice of both strains with an increased and equal capacity to express immunity against GAS as indicated by the reduced level of bacteria in the organs and the ability of vaccinated mice to survive infection. Protection in vaccinated mice was dependent on the presence of T cell-dependent bactericidal antibodies as shown by the ability of serum elicited in immunocompetent mice but not of serum elicited in T cell-deficient nu/nu mice to passively transfer anti-GAS immunity. In conclusion, the results presented here demonstrated that the presence of anti-GAS specific, T cell-dependent bactericidal antibodies elicited after vaccination overcomes the innate genetic susceptibility of C3H/HeN mice and makes both resistant and susceptible mice equally capable of controlling GAS infection.
2007-11-19T13:54:12Z
2007-11-19T13:54:12Z
2006-02-01
Article
Microbes Infect. 2006, 8(2):347-53
1286-4579
16213175
10.1016/j.micinf.2005.06.024
http://hdl.handle.net/10033/14628
en
oai:repository.helmholtz-hzi.de:10033/195322019-08-30T11:25:43Zcom_10033_620618col_10033_620621
2008-03-03T13:32:53Z
urn:hdl:10033/19532
Transcriptome analysis of murine macrophages in response to infection with Streptococcus pyogenes reveals an unusual activation program.
Goldmann, Oliver
von Köckritz-Blickwede, Maren
Höltje, Claudia
Chhatwal, Gursharan S
Geffers, Robert
Medina, Eva
Infection Immunology Research Group, Helmholtz Center for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
The complex response of murine macrophages to infection with Streptococcus pyogenes was investigated at the level of gene expression with a high-density oligomer microarray. More than 400 genes were identified as being differentially regulated. Many of the up-regulated genes encode molecules involved in the immune response and in inflammation, transcription, signaling, apoptosis, the cell cycle, electron transport, and cell adhesion. Of particular interest was the up-regulation of proinflammatory cytokines, typical of the classically activated macrophages (M1 phenotype), such as tumor necrosis factor alpha, interleukin 1 (IL-1), and IL-6, and as well as the up-regulation of anti-inflammatory mediators, such as IL-1 decoy receptor and IL-10, associated with alternative macrophage activation (M2 phenotype). Furthermore, the gene encoding inducible nitric oxide synthase (iNOS), an enzyme typically implicated in classical activation, was not induced in infected macrophages. Instead, the gene encoding arginase, a competitor for the iNOS substrate arginine involved in the alternative activation pathway, was up-regulated in S. pyogenes-infected cells. Thus, the microarray-based gene expression analysis demonstrated that S. pyogenes induces an atypical activation program in macrophages, with some but not all features of the classical or alternative activation phenotypes. The microarray data also suggested that the bactericidal activity of macrophages against S. pyogenes is mediated by phagocyte oxidase, as p47phox was up-regulated in infected cells. Indeed, the in vivo and in vitro killing of S. pyogenes was markedly diminished in the absence of functional phagocyte (p47(phox-/-)) but not in the absence of iNOS (iNOS(-/-)). An understanding of how macrophages respond to S. pyogenes at the molecular level may facilitate the development of new therapeutic paradigms.
2008-03-03T13:32:53Z
2008-03-03T13:32:53Z
2007-08
Article
Transcriptome analysis of murine macrophages in response to infection with Streptococcus pyogenes reveals an unusual activation program. 2007, 75 (8):4148-57 Infect. Immun.
0019-9567
17526748
10.1128/IAI.00181-07
http://hdl.handle.net/10033/19532
Infection and immunity
en
oai:repository.helmholtz-hzi.de:10033/234722019-08-30T11:37:23Zcom_10033_620618col_10033_620621
2008-04-15T13:36:28Z
urn:hdl:10033/23472
Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation.
von Köckritz-Blickwede, Maren
Goldmann, Oliver
Thulin, Pontus
Heinemann, Katja
Norrby-Teglund, Anna
Rohde, Manfred
Medina, Eva
Infection Immunology Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany.
These days it has been increasingly recognized that mast cells (MCs) are critical components of host defense against pathogens. In this study, we have provided the first evidence that MCs can kill bacteria by entrapping them in extracellular structures similar to the extracellular traps described for neutrophils (NETs). We took advantage of the ability of MCs to kill the human pathogen Streptococcus pyogenes by a phagocytosis-independent mechanism in order to characterize the extracellular antimicrobial activity of MCs. Close contact of bacteria and MCs was required for full antimicrobial activity. Immunofluorescence and electron microscopy revealed that S pyogenes was entrapped by extracellular structures produced by MCs (MCETs), which are composed of DNA, histones, tryptase, and the antimicrobial peptide LL-37. Disruption of MCETs significantly reduced the antimicrobial effect of MCs, suggesting that intact extracellular webs are critical for effective inhibition of bacterial growth. Similar to NETs, production of MCETs was mediated by a reactive oxygen species (ROS)-dependent cell death mechanism accompanied by disruption of the nuclear envelope, which can be induced after stimulation of MCs with phorbol-12-myristate-13-acetate (PMA), H(2)O(2), or bacterial pathogens. Our study provides the first experimental evidence of antimicrobial extracellular traps formation by an immune cell population other than neutrophils.
2008-04-15T13:36:28Z
2008-04-15T13:36:28Z
2008-03-15
Article
Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. 2008, 111 (6):3070-80 Blood
0006-4971
18182576
10.1182/blood-2007-07-104018
http://hdl.handle.net/10033/23472
Blood
en
oai:repository.helmholtz-hzi.de:10033/243722019-08-30T11:33:57Zcom_10033_620618col_10033_620621
2008-04-29T09:14:07Z
urn:hdl:10033/24372
Contribution of interleukin-6/gp 130 signaling in hepatocytes to the inflammatory response in mice infected with Streptococcus pyogenes.
Klein, Christian
Medina, Eva
Sander, Leif
Dierssen, Uta
Roskams, Tania
Mueller, Werner
Trautwein, Christian
Goldmann, Oliver
Medizinische Klinik III, University Hospital Aachen, Rheinisch-Westfalisch Techniche Hochschule Aachen, Aachen, Germany. christian.klein@dife.de
BACKGROUND: Sepsis and septic shock caused by gram-positive bacteria have become increasingly frequent clinical problems. These conditions are accompanied by an overwhelming inflammation in which the liver plays a central role as a source and target of inflammatory mediators. Sepsis is still associated with high mortality rates, and new intervention strategies directed at ameliorating the extent of the inflammatory reaction are strongly needed. Here, we investigated whether blockage of the transducer gp130, a receptor involved in the regulation of the inflammatory response, might be useful in the treatment of experimental gram-positive sepsis. METHODS: An experimental model of gram-positive sepsis was used in which liver-specific gp130-deficient mice (FVB/n alfpCre+ gp130(LoxP/LoxP)) and wild-type mice (FVB/n gp130(LoxP/LoxP)) were intravenously infected with Streptococcus pyogenes. The following parameters were monitored: mortality, bacterial loads in systemic organs, serum inflammatory cytokine levels, and organ damage. RESULTS: We show that infected gp130-deficient mice survived significantly longer, had lower bacterial loads, and developed organ damage more slowly than infected wild-type mice. Furthermore, levels of interferon- gamma , interleukin-6, and the chemokine cytokine-induced neutrophil chemoattractant were significantly lower in gp130-deficient mice than in wild-type mice. Histopathological examination of livers showed lower amounts of neutrophil infiltration, apoptosis, and tissue damage in infected gp130-deficient mice than in wild-type mice. CONCLUSION: Our results demonstrate that the gp130 receptor is involved in the regulation of inflammation during gram-positive sepsis and that blockage of gp130 signaling in hepatocytes could constitute a novel target for adjunctive therapy in patients with sepsis.
2008-04-29T09:14:07Z
2008-04-29T09:14:07Z
2007-09-01
Article
Contribution of interleukin-6/gp 130 signaling in hepatocytes to the inflammatory response in mice infected with Streptococcus pyogenes. 2007, 196 (5):755-62 J. Infect. Dis.
0022-1899
17674319
10.1086/520090
http://hdl.handle.net/10033/24372
The Journal of infectious diseases
en
oai:repository.helmholtz-hzi.de:10033/483142019-08-30T11:30:58Zcom_10033_620618col_10033_620621
2009-02-02T08:57:16Z
urn:hdl:10033/48314
Immune recognition of Streptococcus pyogenes by dendritic cells.
Loof, Torsten G
Goldmann, Oliver
Medina, Eva
Infection Immunology Research Group, Department of Microbial Pathogenesis, Helmholtz Center for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
Streptococcus pyogenes is one of the most frequent human pathogens. Recent studies have identified dendritic cells (DCs) as important contributors to host defense against S. pyogenes. The objective of this study was to identify the receptors involved in immune recognition of S. pyogenes by DCs. To determine whether Toll-like receptors (TLRs) were involved in DC sensing of S. pyogenes, we evaluated the response of bone marrow-derived DCs obtained from mice deficient in MyD88, an adapter molecule used by almost all TLRs, following S. pyogenes stimulation. Despite the fact that MyD88(-/-) DCs did not differ from wild-type DCs in the ability to internalize and kill S. pyogenes, the up-regulation of maturation markers, such as CD40, CD80, and CD86, and the production of inflammatory cytokines, such as interleukin-12 (IL-12), IL-6, and tumor necrosis factor alpha, were dramatically impaired in S. pyogenes-stimulated MyD88(-/-) DCs. These results suggest that signaling through TLRs is the principal pathway by which DCs sense S. pyogenes and become activated. Surprisingly, DCs deficient in signaling through each of the TLRs reported as potential receptors for gram-positive cell components, such as TLR1, TLR2, TLR4, TLR9, and TLR2/6, were not impaired in the secretion of proinflammatory cytokines and the up-regulation of costimulatory molecules after S. pyogenes stimulation. In conclusion, our results exclude a major involvement of a single TLR or the heterodimer TLR2/6 in S. pyogenes sensing by DCs and argue for a multimodal recognition in which a combination of several different TLR-mediated signals is essential for a rapid and effective response to the pathogen.
2009-02-02T08:57:16Z
2009-02-02T08:57:16Z
2008-06
Article
Immune recognition of Streptococcus pyogenes by dendritic cells. 2008, 76 (6):2785-92 Infect. Immun.
1098-5522
18391010
10.1128/IAI.01680-07
http://hdl.handle.net/10033/48314
Infection and immunity
en
oai:repository.helmholtz-hzi.de:10033/980202019-08-30T11:25:11Zcom_10033_620618col_10033_620621
2010-05-06T09:45:30Z
urn:hdl:10033/98020
Age-related susceptibility to Streptococcus pyogenes infection in mice: underlying immune dysfunction and strategy to enhance immunity.
Goldmann, Oliver
Lehne, Sabine
Medina, Eva
Infection Immunology Research Group, Department of Microbial Pathogenesis, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, D-38124 Braunschweig, Germany.
Epidemiological studies have shown that the elderly are at higher risk of severe Streptococcus pyogenes infections. In this study, we used a mouse model that displays the age-related loss of resistance to S. pyogenes infection seen in humans to investigate the impaired immune mechanism underlying the age-associated susceptibility to this pathogen. Young (2-3 months old) and aged (>20 months old) BALB/c mice were subcutaneously or intravenously inoculated with S. pyogenes and their capacity to control infection was compared. Aged mice showed faster progression of disease, earlier morbidity, and increased mortality when compared with young animals. Since macrophages are critical for host defence against S. pyogenes, we investigated whether susceptibility of aged mice may be due to an age-associated decline in the functionality of these cells. Our results showed that macrophages from aged mice were as capable as those from young animals to uptake and kill S. pyogenes, but the number of resident tissue macrophages was significantly reduced in the aged host. Treatment of aged mice with macrophage colony-stimulating factor (M-CSF) significantly increased the number of resident macrophages and improved their response to infection. Our results indicate that treatment with M-CSF can restore, at least in part, the mechanisms affected by immunosenescence and enhance the natural resistance of aged mice to infection with S. pyogenes.
2010-05-06T09:45:30Z
2010-05-06T09:45:30Z
2010-04
Article
Age-related susceptibility to Streptococcus pyogenes infection in mice: underlying immune dysfunction and strategy to enhance immunity. 2010, 220 (5):521-9 J. Pathol.
1096-9896
20020512
10.1002/path.2664
http://hdl.handle.net/10033/98020
The Journal of pathology
en
oai:repository.helmholtz-hzi.de:10033/2039692019-08-30T11:36:32Zcom_10033_620618col_10033_620621
2012-01-20T14:48:05Z
urn:hdl:10033/203969
Subcutaneous infection with S. aureus in mice reveals association of resistance with influx of neutrophils and Th2 response.
Nippe, Nadine
Varga, Georg
Holzinger, Dirk
Löffler, Bettina
Medina, Eva
Becker, Karsten
Roth, Johannes
Ehrchen, Jan M
Sunderkötter, Cord
Institute of Immunology, University of Muenster, Muenster, Germany.
Staphylococcus aureus is the leading cause of bacterial skin infection. Once it overcomes the epithelial barrier, it either remains locally controlled or spreads in the dermis causing soft tissue infection. These different courses depend not only on its virulence factors, but also on the immune response of the infected individual. The goal of this study was to identify host factors that influence different outcomes. We, therefore, established comparative analysis of subcutaneous footpad infection with S. aureus (SH1000) in different inbred mouse strains. We found that C57BL/6 mice are more susceptible than BALB/c and DBA/2 mice, reflected by significantly higher footpad swelling and bacterial load, as well as increased dissemination of bacteria into inguinal lymph nodes and kidneys. This susceptibility was associated with lower influx of polymorphonuclear leukocytes (PMNs), but higher secretion of CXCL-2. Remarkably, resistance correlated with S. aureus-specific Th2-cell response in BALB/c and DBA/2 mice, whereas susceptible C57BL/6 mice generated a Th1-cell response. As Th1 cells are able to induce release of CXCL-2, and as CXCL-2 is able to increase the survival of S. aureus within PMNs, interactions between PMNs and Th1 or Th2 cells need to be considered as important mechanisms of resistance in murine soft tissue infection with S. aureus.
2012-01-20T14:48:05Z
2012-01-20T14:48:05Z
2011-01
Article
Subcutaneous infection with S. aureus in mice reveals association of resistance with influx of neutrophils and Th2 response. 2011, 131 (1):125-32 J. Invest. Dermatol.
1523-1747
20882039
10.1038/jid.2010.282
http://hdl.handle.net/10033/203969
The Journal of investigative dermatology
en
oai:repository.helmholtz-hzi.de:10033/2146692019-08-30T11:31:49Zcom_10033_620618col_10033_620621
2012-03-07T15:14:34Z
urn:hdl:10033/214669
Staphylococcus aureus evades the extracellular antimicrobial activity of mast cells by promoting its own uptake.
Abel, Jens
Goldmann, Oliver
Ziegler, Christina
Höltje, Claudia
Smeltzer, Mark S
Cheung, Ambrose L
Bruhn, Daniela
Rohde, Manfred
Medina, Eva
Infection Immunology Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
In this study, we investigated the interactions of Staphylococcus aureus with mast cells, which are multifunctional sentinels lining the surfaces of the body. We found that bone marrow-derived murine mast cells (BMMC) exerted a powerful phagocytosis-independent antimicrobial activity against S. aureus. Both the release of extracellular traps as well as discharge of antimicrobial compounds were the mechanisms used by the BMMC to kill extracellular S. aureus. This was accompanied by the secretion of mediators such as TNF-α involved in the recruitment of effector cells. Interestingly, S. aureus subverted the extracellular antimicrobial activity of the BMMC by internalizing within these cells. S. aureus was also capable to internalize within human mast cells (HMC-1) and within murine skin mast cells during in vivo infection. Bacteria internalization was, at least in part, mediated by the α5β1 integrins expressed on the surface of the mast cell. In the intracellular milieu, the bacterium survived and persisted by increasing the cell wall thickness and by gaining access into the mast cell cytosol. The expression of α-hemolysin was essential for staphylococci intracellular persistence. By hiding within the long-life mast cells, staphylococci not only avoid clearance but also establish an infection reservoir that could contribute to chronic carriage.
2012-03-07T15:14:34Z
2012-03-07T15:14:34Z
2011
Article
Staphylococcus aureus evades the extracellular antimicrobial activity of mast cells by promoting its own uptake. 2011, 3 (5):495-507 J Innate Immun
1662-8128
21654154
10.1159/000327714
http://hdl.handle.net/10033/214669
Journal of innate immunity
en
oai:repository.helmholtz-hzi.de:10033/2515592019-08-30T11:24:31Zcom_10033_620618col_10033_620621
2012-11-09T12:36:20Z
urn:hdl:10033/251559
Global transcriptome analysis in influenza-infected mouse lungs reveals the kinetics of innate and adaptive host immune responses.
Pommerenke, Claudia
Wilk, Esther
Srivastava, Barkha
Schulze, Annika
Novoselova, Natalia
Geffers, Robert
Schughart, Klaus
Department of Infection Genetics, Helmholtz Centre for Infection Research and University of Veterinary Medicine Hannover, Braunschweig, Germany.
An infection represents a highly dynamic process involving complex biological responses of the host at many levels. To describe such processes at a global level, we recorded gene expression changes in mouse lungs after a non-lethal infection with influenza A virus over a period of 60 days. Global analysis of the large data set identified distinct phases of the host response. The increase in interferon genes and up-regulation of a defined NK-specific gene set revealed the initiation of the early innate immune response phase. Subsequently, infiltration and activation of T and B cells could be observed by an augmentation of T and B cell specific signature gene expression. The changes in B cell gene expression and preceding chemokine subsets were associated with the formation of bronchus-associated lymphoid tissue. In addition, we compared the gene expression profiles from wild type mice with Rag2 mutant mice. This analysis readily demonstrated that the deficiency in the T and B cell responses in Rag2 mutants could be detected by changes in the global gene expression patterns of the whole lung. In conclusion, our comprehensive gene expression study describes for the first time the entire host response and its kinetics to an acute influenza A infection at the transcriptome level.
2012-11-09T12:36:20Z
2012-11-09T12:36:20Z
2012
Article
Global transcriptome analysis in influenza-infected mouse lungs reveals the kinetics of innate and adaptive host immune responses. 2012, 7 (7):e41169 PLoS ONE
1932-6203
22815957
10.1371/journal.pone.0041169
http://hdl.handle.net/10033/251559
PloS one
en
Archived with thanks to PloS one
oai:repository.helmholtz-hzi.de:10033/2690322019-08-30T11:26:13Zcom_10033_620618col_10033_620621
2013-02-11T15:37:53Z
urn:hdl:10033/269032
The expanding world of extracellular traps: not only neutrophils but much more.
Goldmann, Oliver
Medina, Eva
Infection Immunology Research Group, Helmholtz Centre for Infection Research Braunschweig, Germany.
The release of extracellular traps (ETs) is a recently described mechanism of innate immune response to infection. Although ETs have been intensely investigated in the context of neutrophil antimicrobial effector mechanisms, other immune cells such as mast cells, eosinophils, and macrophages can also release these structures. The different ETs have several features in common, regardless of the type of cells from which they originated, including a DNA backbone with embedded antimicrobial peptides, proteases, and histones. However, they also exhibit remarkable individual differences such as the type of sub-cellular compartments from where the DNA backbone originates (e.g., nucleus or mitochondria), the proportion of responding cells within the pool, and/or the molecular mechanism/s underlying the ETs formation. This review summarizes the knowledge accumulated in recent years regarding the complex and expanding world of ETs and their role in immune function with particular emphasis on the role of other immune cells rather than on neutrophils exclusively.
2013-02-11T15:37:53Z
2013-02-11T15:37:53Z
2012
Article
The expanding world of extracellular traps: not only neutrophils but much more. 2012, 3:420 Front Immunol
1664-3224
23335924
10.3389/fimmu.2012.00420
http://hdl.handle.net/10033/269032
Frontiers in immunology
en
Archived with thanks to Frontiers in immunology
oai:repository.helmholtz-hzi.de:10033/2950522019-08-30T11:26:42Zcom_10033_620618col_10033_620621
2013-07-02T14:25:10Z
urn:hdl:10033/295052
Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia.
Rosendahl, Alva
Bergmann, Simone
Hammerschmidt, Sven
Goldmann, Oliver
Medina, Eva
Infection Immunology Research Group, Department of Medical Microbiology, Helmholtz Centre for Infection Research Braunschweig, Germany.
Streptococcus pneumoniae is a leading cause of bacterial pneumonia worldwide. Given the critical role of dendritic cells (DCs) in regulating and modulating the immune response to pathogens, we investigated here the role of DCs in S. pneumoniae lung infections. Using a well-established transgenic mouse line which allows the conditional transient depletion of DCs, we showed that ablation of DCs resulted in enhanced resistance to intranasal challenge with S. pneumoniae. DCs-depleted mice exhibited delayed bacterial systemic dissemination, significantly reduced bacterial loads in the infected organs and lower levels of serum inflammatory mediators than non-depleted animals. The increased resistance of DCs-depleted mice to S. pneumoniae was associated with a better capacity to restrict pneumococci extrapulmonary dissemination. Furthermore, we demonstrated that S. pneumoniae disseminated from the lungs into the regional lymph nodes in a cell-independent manner and that this direct way of dissemination was much more efficient in the presence of DCs. We also provide evidence that S. pneumoniae induces expression and activation of matrix metalloproteinase-9 (MMP-9) in cultured bone marrow-derived DCs. MMP-9 is a protease involved in the breakdown of extracellular matrix proteins and is critical for DC trafficking across extracellular matrix and basement membranes during the migration from the periphery to the lymph nodes. MMP-9 was also significantly up-regulated in the lungs of mice after intranasal infection with S. pneumoniae. Notably, the expression levels of MMP-9 in the infected lungs were significantly decreased after depletion of DCs suggesting the involvement of DCs in MMP-9 production during pneumococcal pneumonia. Thus, we propose that S. pneumoniae can exploit the DC-derived proteolysis to open tissue barriers thereby facilitating its own dissemination from the local site of infection.
2013-07-02T14:25:10Z
2013-07-02T14:25:10Z
2013
Article
Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia. 2013, 3:21 Front Cell Infect Microbiol
2235-2988
23802100
10.3389/fcimb.2013.00021
http://hdl.handle.net/10033/295052
Frontiers in cellular and infection microbiology
en
Archived with thanks to Frontiers in cellular and infection microbiology
oai:repository.helmholtz-hzi.de:10033/3110592019-08-30T11:37:00Zcom_10033_620618col_10033_620621
2014-01-08T09:58:11Z
urn:hdl:10033/311059
Phagocytosis Escape by a Staphylococcus aureus Protein That Connects Complement and Coagulation Proteins at the Bacterial Surface.
Ko, Ya-Ping
Kuipers, Annemarie
Freitag, Claudia M
Jongerius, Ilse
Medina, Eva
van Rooijen, Willemien J
Spaan, András N
van Kessel, Kok P M
Höök, Magnus
Rooijakkers, Suzan H M
RG Infection immunology, Helmholtz Centre for infection research (HZI), Inhoffenstr. 7, D-38125 Braunschweig, Germany
Upon contact with human plasma, bacteria are rapidly recognized by the complement system that labels their surface for uptake and clearance by phagocytic cells. Staphylococcus aureus secretes the 16 kD Extracellular fibrinogen binding protein (Efb) that binds two different plasma proteins using separate domains: the Efb N-terminus binds to fibrinogen, while the C-terminus binds complement C3. In this study, we show that Efb blocks phagocytosis of S. aureus by human neutrophils. In vitro, we demonstrate that Efb blocks phagocytosis in plasma and in human whole blood. Using a mouse peritonitis model we show that Efb effectively blocks phagocytosis in vivo, either as a purified protein or when produced endogenously by S. aureus. Mutational analysis revealed that Efb requires both its fibrinogen and complement binding residues for phagocytic escape. Using confocal and transmission electron microscopy we show that Efb attracts fibrinogen to the surface of complement-labeled S. aureus generating a 'capsule'-like shield. This thick layer of fibrinogen shields both surface-bound C3b and antibodies from recognition by phagocytic receptors. This information is critical for future vaccination attempts, since opsonizing antibodies may not function in the presence of Efb. Altogether we discover that Efb from S. aureus uniquely escapes phagocytosis by forming a bridge between a complement and coagulation protein.
2014-01-08T09:58:11Z
2014-01-08T09:58:11Z
2013-12
Article
Phagocytosis Escape by a Staphylococcus aureus Protein That Connects Complement and Coagulation Proteins at the Bacterial Surface. 2013, 9 (12):e1003816 PLoS Pathog.
1553-7374
24348255
10.1371/journal.ppat.1003816
http://hdl.handle.net/10033/311059
PLoS pathogens
en
Archived with thanks to PLoS pathogens
oai:repository.helmholtz-hzi.de:10033/3112022019-08-30T11:37:00Zcom_10033_620618col_10033_620621
2014-01-10T10:33:53Z
urn:hdl:10033/311202
Prognostic value and therapeutic potential of TREM-1 in Streptococcus pyogenes- induced sepsis.
Horst, Sarah A
Linnér, Anna
Beineke, Andreas
Lehne, Sabine
Höltje, Claudia
Hecht, Alexander
Norrby-Teglund, Anna
Medina, Eva
Dep. of infection immunology, Helmholtz Centre for infection research, Braunschweig, Germany
TREM-1 (triggering receptor expressed on myeloid cells) is a surface molecule expressed on neutrophils and macrophages which has been implicated in the amplification of inflammatory responses triggered during infection. In the present study, we have investigated the clinical significance of TREM-1 in Streptococcus pyogenes-induced severe sepsis in both experimentally infected mice as well as in patients with streptococcal toxic shock. We found that S. pyogenes induced a dose-dependent upregulation of TREM-1 in in vitro cultured phagocytic cells and in the organs of S. pyogenes-infected mice. Furthermore, we reported a positive correlation between serum levels of soluble TREM-1 (sTREM-1) and disease severity in infected patients as well as in experimentally infected mice. Hence, sTREM-1 may represent a useful surrogate marker for streptococcal sepsis. We found that modulation of TREM-1 by administration of the TREM-1 decoy receptor rTREM-1/Fc substantially attenuated the synthesis of inflammatory cytokines. More importantly, treatment of S. pyogenes-infected septic mice with rTREM-1/Fc or the synthetically produced conserved extracellular domain LP17 significantly improved disease outcome. In summary, our data suggest that TREM-1 may not only represent a valuable marker for S. pyogenes infection severity but it may also be an attractive target for the treatment of streptococcal sepsis.
2014-01-10T10:33:53Z
2014-01-10T10:33:53Z
2013
Article
Prognostic value and therapeutic potential of TREM-1 in Streptococcus pyogenes- induced sepsis. 2013, 5 (6):581-90 J Innate Immun
1662-8128
23571837
10.1159/000348283
http://hdl.handle.net/10033/311202
Journal of innate immunity
en
Archived with thanks to Journal of innate immunity
oai:repository.helmholtz-hzi.de:10033/3328552019-08-30T11:27:16Zcom_10033_620618col_10033_620621
2014-10-17T09:01:15Z
urn:hdl:10033/332855
The role of coagulation/fibrinolysis during Streptococcus pyogenes infection.
Loof, Torsten G
Deicke, Christin
Medina, Eva
Helmholtz Centre for infection research, Inhoffenstr. 7, D38124 Braunschweig, Germany.
The hemostatic system comprises platelet aggregation, coagulation and fibrinolysis and is a host defense mechanism that protects the integrity of the vascular system after tissue injury. During bacterial infections, the coagulation system cooperates with the inflammatory system to eliminate the invading pathogens. However, pathogenic bacteria have frequently evolved mechanisms to exploit the hemostatic system components for their own benefit. Streptococcus pyogenes, also known as Group A Streptococcus, provides a remarkable example of the extraordinary capacity of pathogens to exploit the host hemostatic system to support microbial survival and dissemination. The coagulation cascade comprises the contact system (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway), both leading to fibrin formation. During the early phase of S. pyogenes infection, the activation of the contact system eventually leads to bacterial entrapment within a fibrin clot, where S. pyogenes is immobilized and killed. However, entrapped S. pyogenes can circumvent the antimicrobial effect of the clot by sequestering host plasminogen on the bacterial cell surface that, after conversion into its active proteolytic form, plasmin, degrades the fibrin network and facilitates the liberation of S. pyogenes from the clot. Furthermore, the surface-localized fibrinolytic activity also cleaves a variety of extracellular matrix proteins, thereby enabling S. pyogenes to migrate across barriers and disseminate within the host. This review summarizes the knowledge gained during the last two decades on the role of coagulation/fibrinolysis in host defense against S. pyogenes as well as the strategies developed by this pathogen to evade and exploit these host mechanisms for its own benefit.
2014-10-17T09:01:15Z
2014-10-17T09:01:15Z
2014
Article
The role of coagulation/fibrinolysis during Streptococcus pyogenes infection. 2014, 4:128 Front Cell Infect Microbiol
2235-2988
25309880
10.3389/fcimb.2014.00128
http://hdl.handle.net/10033/332855
Frontiers in cellular and infection microbiology
Archived with thanks to Frontiers in cellular and infection microbiology
oai:repository.helmholtz-hzi.de:10033/3468782019-08-30T11:26:13Zcom_10033_620618col_10033_620621
2015-03-19T09:21:47Z
urn:hdl:10033/346878
Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection.
Tuchscherr, Lorena
Medina, Eva
Hussain, Muzaffar
Völker, Wolfgang
Heitmann, Vanessa
Niemann, Silke
Holzinger, Dirk
Roth, Johannes
Proctor, Richard A
Becker, Karsten
Peters, Georg
Löffler, Bettina
Staphylococcus aureus is a frequent cause for serious, chronic and therapy-refractive infections in spite of susceptibility to antibiotics in vitro. In chronic infections, altered bacterial phenotypes, such as small colony variants (SCVs), have been found. Yet, it is largely unclear whether the ability to interconvert from the wild-type to the SCV phenotype is only a rare clinical and/or just laboratory phenomenon or is essential to sustain an infection. Here, we performed different long-term in vitro and in vivo infection models with S. aureus and we show that viable bacteria can persist within host cells and/or tissues for several weeks. Persistence induced bacterial phenotypic diversity, including SCV phenotypes, accompanied by changes in virulence factor expression and auxotrophism. However, the recovered SCV phenotypes were highly dynamic and rapidly reverted to the fully virulent wild-type form when leaving the intracellular location and infecting new cells. Our findings demonstrate that bacterial phenotype switching is an integral part of the infection process that enables the bacteria to hide inside host cells, which can be a reservoir for chronic and therapy-refractive infections.
2015-03-19T09:21:47Z
2015-03-19T09:21:47Z
2011-03
Article
Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection. 2011, 3 (3):129-41 EMBO Mol Med
1757-4684
21268281
10.1002/emmm.201000115
http://hdl.handle.net/10033/346878
EMBO molecular medicine
en
oai:repository.helmholtz-hzi.de:10033/5759292019-08-30T11:28:24Zcom_10033_620618col_10033_620621
2015-08-25T12:44:17Z
urn:hdl:10033/575929
High-resolution transcriptomic analysis of the adaptive response of Staphylococcus aureus during acute and chronic phases of osteomyelitis.
Szafranska, Anna K
Oxley, Andrew P A
Chaves-Moreno, Diego
Horst, Sarah A
Roßlenbroich, Steffen
Peters, Georg
Goldmann, Oliver
Rohde, Manfred
Sinha, Bhanu
Pieper, Dietmar H
Löffler, Bettina
Jauregui, Ruy
Wos-Oxley, Melissa L
Medina, Eva
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Osteomyelitis is a difficult-to-eradicate bone infection typically caused by Staphylococcus aureus. In this study, we investigated the in vivo transcriptional adaptation of S. aureus during bone infection. To this end, we determined the transcriptome of S. aureus during the acute (day 7) and chronic (day 28) phases of experimental murine osteomyelitis using RNA sequencing (RNA-Seq). We identified a total of 180 genes significantly more highly expressed by S. aureus during acute or chronic in vivo infection than under in vitro growth conditions. These genes encoded proteins involved in gluconeogenesis, proteolysis of host proteins, iron acquisition, evasion of host immune defenses, and stress responses. At the regulatory level, sarA and -R and saeR and -S as well as the small RNA RsaC were predominantly expressed by S. aureus during in vivo infection. Only nine genes, including the genes encoding the arginine deiminase (ADI) pathway and those involved in the stringent response, were significantly more highly expressed by S. aureus during the chronic than the acute stage of infection. Analysis by quantitative reverse transcription-PCR (qRT-PCR) of a subset of these in vivo-expressed genes in clinical specimens yielded the same results as those observed in the murine system. Collectively, our results show that during acute osteomyelitis, S. aureus induced the transcription of genes that mediate metabolic adaptation, immune evasion, and replication. During the chronic phase, however, S. aureus switched its transcriptional response from a proliferative to a persistence mode, probably driven by the severe deficiency in nutrient supplies. Interfering with the survival strategies of S. aureus during chronic infection could lead to more effective treatments.
2015-08-25T12:44:17Z
2015-08-25T12:44:17Z
2014
Article
High-resolution transcriptomic analysis of the adaptive response of Staphylococcus aureus during acute and chronic phases of osteomyelitis. 2014, 5 (6): MBio
2150-7511
25538190
10.1128/mBio.01775-14
http://hdl.handle.net/10033/575929
mBio
en
oai:repository.helmholtz-hzi.de:10033/5818092019-08-30T11:29:17Zcom_10033_620618col_10033_620621
2015-11-05T12:26:40Z
urn:hdl:10033/581809
Genome sequence of the pink-pigmented marine bacterium Loktanella hongkongensis type strain (UST950701-009P(T)), a representative of the Roseobacter group.
Lau, Stanley Ck
Riedel, Thomas
Fiebig, Anne
Han, James
Huntemann, Marcel
Petersen, Jörn
Ivanova, Natalia N
Markowitz, Victor
Woyke, Tanja
Göker, Markus
Kyrpides, Nikos C
Klenk, Hans-Peter
Qian, Pei-Yuan
Loktanella hongkongensis UST950701-009P(T) is a Gram-negative, non-motile and rod-shaped bacterium isolated from a marine biofilm in the subtropical seawater of Hong Kong. When growing as a monospecies biofilm on polystyrene surfaces, this bacterium is able to induce larval settlement and metamorphosis of a ubiquitous polychaete tubeworm Hydroides elegans. The inductive cues are low-molecular weight compounds bound to the exopolymeric matrix of the bacterial cells. In the present study we describe the features of L. hongkongensis strain DSM 17492(T) together with its genome sequence and annotation and novel aspects of its phenotype. The 3,198,444 bp long genome sequence encodes 3104 protein-coding genes and 57 RNA genes. The two unambiguously identified extrachromosomal replicons contain replication modules of the RepB and the Rhodobacteraceae-specific DnaA-like type, respectively.
2015-11-05T12:26:40Z
2015-11-05T12:26:40Z
2015
Article
Genome sequence of the pink-pigmented marine bacterium Loktanella hongkongensis type strain (UST950701-009P(T)), a representative of the Roseobacter group. 2015, 10:51 Stand Genomic Sci
1944-3277
26380639
10.1186/s40793-015-0050-9
http://hdl.handle.net/10033/581809
Standards in genomic sciences
en
oai:repository.helmholtz-hzi.de:10033/5957202019-08-30T11:36:05Zcom_10033_620618col_10033_620621
2016-02-05T15:15:11Z
urn:hdl:10033/595720
Global Regulation of Gene Expression by the MafR Protein of Enterococcus faecalis.
Ruiz-Cruz, Sofía
Espinosa, Manuel
Goldmann, Oliver
Bravo, Alicia
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
Enterococcus faecalis is a natural inhabitant of the human gastrointestinal tract. However, as an opportunistic pathogen, it is able to colonize other host niches and cause life-threatening infections. Its adaptation to new environments involves global changes in gene expression. The EF3013 gene (here named mafR) of E. faecalis strain V583 encodes a protein (MafR, 482 residues) that has sequence similarity to global response regulators of the Mga/AtxA family. The enterococcal OG1RF genome also encodes the MafR protein (gene OG1RF_12293). In this work, we have identified the promoter of the mafR gene using several in vivo approaches. Moreover, we show that MafR influences positively the transcription of many genes on a genome-wide scale. The most significant target genes encode components of PTS-type membrane transporters, components of ABC-type membrane transporters, and proteins involved in the metabolism of carbon sources. Some of these genes were previously reported to be up-regulated during the growth of E. faecalis in blood and/or in human urine. Furthermore, we show that a mafR deletion mutant strain induces a significant lower degree of inflammation in the peritoneal cavity of mice, suggesting that enterococcal cells deficient in MafR are less virulent. Our work indicates that MafR is a global transcriptional regulator. It might facilitate the adaptation of E. faecalis to particular host niches and, therefore, contribute to its potential virulence.
2016-02-05T15:15:11Z
2016-02-05T15:15:11Z
2015
Article
Global Regulation of Gene Expression by the MafR Protein of Enterococcus faecalis. 2015, 6:1521 Front Microbiol
1664-302X
26793169
10.3389/fmicb.2015.01521
http://hdl.handle.net/10033/595720
Frontiers in microbiology
en
oai:repository.helmholtz-hzi.de:10033/6106742019-08-30T11:28:24Zcom_10033_620618col_10033_620621
2016-05-25T08:54:40Z
urn:hdl:10033/610674
Iron-chelating agent desferrioxamine stimulates formation of neutrophil extracellular traps (NETs) in human blood-derived neutrophils.
Völlger, Lena
Akong-Moore, Kathryn
Cox, Linda
Goldmann, Oliver
Wang, Yanming
Schäfer, Simon T
Naim, Hassan Y
Nizet, Victor
von Köckritz-Blickwede, Maren
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Neutrophil extracellular trap (NET) formation is a significant innate immune defense mechanism against microbial infection that complements other neutrophil functions including phagocytosis and degranulation of antimicrobial peptides. NETs are decondensed chromatin structures in which antimicrobial components (histones, antimicrobial peptides and proteases) are deployed and mediate immobilization of microbes. Here we describe an effect of iron chelation on the phenotype of NET formation. Iron-chelating agent desferrioxamine (DFO) showed a modest but significant induction of NETs by freshly isolated human neutrophils as visualized and quantified by immunocytochemistry against histone-DNA complexes. Further analyses revealed that NET induction by iron chelation required NADPH-dependent production of reactive oxygen species (ROS) as well as protease and peptidyl-arginine-deiminase 4 (PAD4) activities, three key mechanistic pathways previously linked to NET formation. Our results demonstrate that iron chelation by DFO contributes to the formation of NETs and suggest a target for pharmacological manipulation of NET activity.
2016-05-25T08:54:40Z
2016-05-25T08:54:40Z
2016-07
Article
Iron-chelating agent desferrioxamine stimulates formation of neutrophil extracellular traps (NETs) in human blood-derived neutrophils. 2016, 36 (3): Biosci. Rep.
1573-4935
27129288
10.1042/BSR20160031
http://hdl.handle.net/10033/610674
Bioscience reports
en
oai:repository.helmholtz-hzi.de:10033/6143862019-08-30T11:27:16Zcom_10033_620618col_10033_620621
2016-06-23T08:45:45Z
urn:hdl:10033/614386
Differential Contributions of the Complement Anaphylotoxin Receptors C5aR1 and C5aR2 to the Early Innate Immune Response against Staphylococcus aureus Infection.
Horst, Sarah A
Itzek, Andreas
Klos, Andreas
Beineke, Andreas
Medina, Eva
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
The complement anaphylatoxin C5a contributes to host defense against Staphylococcus aureus. In this study, we investigated the functional role of the two known C5a receptors, C5aR1 and C5aR2, in the host response to S. aureus. We found that C5aR1(-/)(-) mice exhibited greater susceptibility to S. aureus bloodstream infection than wild type and C5aR2(-/)(-) mice, as demonstrated by the significantly higher bacterial loads in the kidneys and heart at 24 h of infection, and by the higher levels of inflammatory IL-6 in serum. Histological and immunohistochemistry investigation of infected kidneys at 24 h after bacterial inoculation revealed a discrete infiltration of neutrophils in wild type mice but already well-developed abscesses consisting of bacterial clusters surrounded by a large number of neutrophils in both C5aR1(-/)(-) and C5aR2(-/)(-) mice. Furthermore, blood neutrophils from C5aR1(-/)(-) mice were less efficient than those from wild type or C5aR2(-/)(-) mice at killing S. aureus. The requirement of C5aR1 for efficient killing of S. aureus was also demonstrated in human blood after disrupting C5a-C5aR1 signaling using specific inhibitors. These results demonstrated a role for C5aR1 in S. aureus clearance as well as a role for both C5aR1 and C5aR2 in the orchestration of the inflammatory response during infection.
2016-06-23T08:45:45Z
2016-06-23T08:45:45Z
2015
Article
Differential Contributions of the Complement Anaphylotoxin Receptors C5aR1 and C5aR2 to the Early Innate Immune Response against Staphylococcus aureus Infection. 2015, 4 (4):722-38 Pathogens
2076-0817
26512700
10.3390/pathogens4040722
http://hdl.handle.net/10033/614386
Pathogens (Basel, Switzerland)
en
oai:repository.helmholtz-hzi.de:10033/6208062019-08-30T11:28:49Zcom_10033_620618col_10033_620621
2017-02-03T13:10:34Z
urn:hdl:10033/620806
Host-inherent variability influences the transcriptional response of Staphylococcus aureus during in vivo infection
Thänert, Robert
Goldmann, Oliver
Beineke, Andreas
Medina, Eva
Helmholtz Centre for infection research. Inhoffenstr. 7. 38124 Braunschweig, Germany.
2017-02-03T13:10:34Z
2017-02-03T13:10:34Z
2017-02-03
Article
Host-inherent variability influences the transcriptional response of Staphylococcus aureus during in vivo infection 2017, 8:14268 Nature Communications
2041-1723
10.1038/ncomms14268
http://hdl.handle.net/10033/620806
Nature Communications
http://www.nature.com/doifinder/10.1038/ncomms14268
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6208382019-08-30T11:29:17Zcom_10033_620618col_10033_620621
2017-02-22T15:41:29Z
urn:hdl:10033/620838
Host-inherent variability influences the transcriptional response of Staphylococcus aureus during in vivo infection.
Thänert, Robert
Goldmann, Oliver
Beineke, Andreas
Medina, Eva
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
The rise of antibiotic resistance calls for alternative strategies to treat bacterial infections. One attractive strategy is to directly target bacterial virulence factors with anti-virulence drugs. The expression of virulence traits by pathogens is, however, not constitutive but rather induced by the level of stress encountered within the host. Here we use dual RNA sequencing (RNA-seq) to show that intrinsic variability in the level of host resistance greatly affects the pathogen's transcriptome in vivo. Through analysis of the transcriptional profiles of host and pathogen during Staphylococcus aureus infection of two mouse strains, shown to be susceptible (A/J) or resistant (C57BL/6) to the pathogen, we demonstrate that the expression of virulence factors is dependent on the encountered host resistance. We furthermore provide evidence that this dependence strongly influences the efficacy of anti-virulence strategies, highlighting a potential limitation for the implementation of these strategies.
2017-02-22T15:41:29Z
2017-02-22T15:41:29Z
2017-02-03
Article
Host-inherent variability influences the transcriptional response of Staphylococcus aureus during in vivo infection. 2017, 8:14268 Nat Commun
2041-1723
28155859
10.1038/ncomms14268
http://hdl.handle.net/10033/620838
Nature communications
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210252019-08-30T11:33:57Zcom_10033_620618col_10033_620621
2017-07-31T14:37:09Z
urn:hdl:10033/621025
IL-10 Plays Opposing Roles during Staphylococcus aureus Systemic and Localized Infections.
Leech, John M
Lacey, Keenan A
Mulcahy, Michelle E
Medina, Eva
McLoughlin, Rachel M
IL-10 is a potent anti-inflammatory mediator that plays a crucial role in limiting host immunopathology during bacterial infections by controlling effector T cell activation. Staphylococcus aureus has previously been shown to manipulate the IL-10 response as a mechanism of immune evasion during chronic systemic and biofilm models of infection. In the present study, we demonstrate divergent roles for IL-10 depending on the site of infection. During acute systemic S. aureus infection, IL-10 plays an important protective role and is required to prevent bacterial dissemination and host morbidity by controlling effector T cells and the associated downstream hyperactivation of inflammatory phagocytes, which are capable of host tissue damage. CD19(+)CD11b(+)CD5(+) B1a regulatory cells were shown to rapidly express IL-10 in a TLR2-dependent manner in response to S. aureus, and adoptive transfer of B1a cells was protective during acute systemic infection in IL-10-deficient hosts. In contrast, during localized s.c. infection, IL-10 production plays a detrimental role by facilitating bacterial persistence via the same mechanism of controlling proinflammatory T cell responses. Our findings demonstrate that induction of IL-10 has a major influence on disease outcome during acute S. aureus infection. Too much IL-10 at one end of the scale may suppress otherwise protective T cell responses, thus facilitating persistence of the bacteria, and at the other end, too little IL-10 may tend toward fatal host-mediated pathology through excessive activation of T cells and associated phagocyte-mediated damage.
2017-07-31T14:37:09Z
2017-07-31T14:37:09Z
2017-03-15
Article
IL-10 Plays Opposing Roles during Staphylococcus aureus Systemic and Localized Infections. 2017, 198 (6):2352-2365 J. Immunol.
1550-6606
28167629
10.4049/jimmunol.1601018
http://hdl.handle.net/10033/621025
Journal of immunology (Baltimore, Md. : 1950)
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6211562019-08-30T11:35:39Zcom_10033_620618col_10033_620621
2017-11-02T15:23:27Z
urn:hdl:10033/621156
Identification of a novel subset of myeloid-derived suppressor cells during chronic staphylococcal infection that resembles immature eosinophils.
Goldmann, Oliver
Beineke, Andreas
Medina, Eva
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunchweig, Germany.
We have previously reported that myeloid-derived suppressor cells (MDSC), which are a heterogeneous population of immunosuppressive immature myeloid cells, expanded during chronic Staphylococcus aureus infection and promoted bacterial persistence by inhibiting effector T cells. Two major MDSC subsets including monocytic MDSCs (M-MDSC) and granulocytic MDSCs (G-MDSC) have been described to date. Here, we identified a new subset of MDSC (Eo-MDSC) in S. aureus-infected mice that phenotypically resembles eosinophils. Eo-MDSC exhibit eosinophilic cytoplasmic granules and express CD11b, the eosinophil marker Syglec-F, variable levels of CCR3 and low levels of IL-5R. Furthermore, Eo-MDSC accumulated at the site of infection and exerted a potent immunosuppressive effect on T cell responses that was mediated by nitric oxide-dependent depletion of L-arginine. Increased in the number of Eo-MDSC by adoptive transfer caused a significant exacerbation of infection in S. aureus-infected mice. This study sheds new light on the heterogeneity and complexity of MDSC during chronic infection.
2017-11-02T15:23:27Z
2017-11-02T15:23:27Z
2017-09-23
Article
Identification of a novel subset of myeloid-derived suppressor cells during chronic staphylococcal infection that resembles immature eosinophils. 2017 J. Infect. Dis.
1537-6613
29029332
10.1093/infdis/jix494
http://hdl.handle.net/10033/621156
The Journal of infectious diseases
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212172019-08-30T11:31:23Zcom_10033_338554com_10033_620618col_10033_621787col_10033_620621
2018-01-02T14:17:40Z
urn:hdl:10033/621217
SCM, the M Protein of Streptococcus canis Binds Immunoglobulin G.
Bergmann, Simone
Eichhorn, Inga
Kohler, Thomas P
Hammerschmidt, Sven
Goldmann, Oliver
Rohde, M
Fulde, Marcus
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
The M protein of Streptococcus canis (SCM) is a virulence factor and serves as a surface-associated receptor with a particular affinity for mini-plasminogen, a cleavage product of the broad-spectrum serine protease plasmin. Here, we report that SCM has an additional high-affinity immunoglobulin G (IgG) binding activity. The ability of a particular S. canis isolate to bind to IgG significantly correlates with a scm-positive phenotype, suggesting a dominant role of SCM as an IgG receptor. Subsequent heterologous expression of SCM in non-IgG binding S. gordonii and Western Blot analysis with purified recombinant SCM proteins confirmed its IgG receptor function. As expected for a zoonotic agent, the SCM-IgG interaction is species-unspecific, with a particular affinity of SCM for IgGs derived from human, cats, dogs, horses, mice, and rabbits, but not from cows and goats. Similar to other streptococcal IgG-binding proteins, the interaction between SCM and IgG occurs via the conserved Fc domain and is, therefore, non-opsonic. Interestingly, the interaction between SCM and IgG-Fc on the bacterial surface specifically prevents opsonization by C1q, which might constitute another anti-phagocytic mechanism of SCM. Extensive binding analyses with a variety of different truncated SCM fragments defined a region of 52 amino acids located in the central part of the mature SCM protein which is important for IgG binding. This binding region is highly conserved among SCM proteins derived from different S. canis isolates but differs significantly from IgG-Fc receptors of S. pyogenes and S. dysgalactiae sub. equisimilis, respectively. In summary, we present an additional role of SCM in the pathogen-host interaction of S. canis. The detailed analysis of the SCM-IgG interaction should contribute to a better understanding of the complex roles of M proteins in streptococcal pathogenesis.
2018-01-02T14:17:40Z
2018-01-02T14:17:40Z
2017
Article
SCM, the M Protein of Streptococcus canis Binds Immunoglobulin G. 2017, 7:80 Front Cell Infect Microbiol
2235-2988
28401063
10.3389/fcimb.2017.00080
http://hdl.handle.net/10033/621217
Frontiers in cellular and infection microbiology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213952019-08-30T11:27:41Zcom_10033_620618col_10033_620621
2018-06-12T13:33:16Z
urn:hdl:10033/621395
Changed Expression of Cytoskeleton Proteins During Lung Injury in a Mouse Model of Infection.
Ferrer-Navarro, Mario
Strehlitz, Anja
Medina, Eva
Vila, Jordi
DIGE
Streptococcus pneumoniae
cytoskeleton
lung injury
pneumonia
Infections by are a major cause of morbidity and mortality worldwide, often causing community-acquired pneumonia, otitis media and also bacteremia and meningitis. Studies on are mainly focused on its virulence or capacity to evade the host immune system, but little is known about the injury caused in lungs during a pneumococcal infection. Herein we investigated this issue comparing the proteome profile of lungs from infected mice with control mice by means of difference gel electrophoresis (DIGE) technology. In order to obtain reliable results three biological replicas were used, and four technical replicas were carried out in each biological replica. Proteomic comparison was performed at two time points: 24 and 48 h post infection. A total of 91 proteins were identified with different abundance. We found important changes in the protein profiles during pneumococcal infection mainly associated with regulation of vesicle-mediated transport, wound healing, and cytoskeleton organization. In conclusion, the results obtained show that the cytoskeleton of the host cell is modified in infection.
2018-06-12T13:33:16Z
2018-06-12T13:33:16Z
Article
29867838
10.3389/fmicb.2018.00928
http://hdl.handle.net/10033/621395
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
oai:repository.helmholtz-hzi.de:10033/6214972019-08-30T11:30:31Zcom_10033_620618col_10033_620621
2018-09-26T12:17:08Z
urn:hdl:10033/621497
Zirconyl Clindamycinphosphate Antibiotic Nanocarriers for Targeting Intracellular Persisting
Heck, Joachim G.
Rox, Katharina
Lünsdorf, Heinrich
Lückerath, Thorsten
Klaassen, Nicole
Medina, Eva
Goldmann, Oliver
Feldmann, Claus
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
[ZrO]2+[CLP]2– (CLP: clindamycinphosphate) inorganic–organic hybrid nanoparticles (IOH-NPs) represent a novel strategy to treat persisting, recurrent infections with multiresistant Staphylococcus aureus. [ZrO]2+[CLP]2– is prepared in water and contains the approved antibiotic with unprecedented high load (82 wt % CLP per nanoparticle). The IOH-NPs result in 70–150-times higher antibiotic concentrations at difficult-to-reach infection sites, offering new options for improved drug delivery for chronic and difficult-to-treat infections.
2018-09-26T12:17:08Z
2018-09-26T12:17:08Z
Article
2470-1343
2470-1343
10.1021/acsomega.8b00637
http://hdl.handle.net/10033/621497
http://pubs.acs.org/doi/10.1021/acsomega.8b00637
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
3
8
8589
8594
ACS Omega
oai:repository.helmholtz-hzi.de:10033/6215772019-08-30T11:29:43Zcom_10033_620618col_10033_620621
2018-11-21T14:17:19Z
urn:hdl:10033/621577
Fluorescent Inorganic-Organic Hybrid Nanoparticles
Neumeier, B. Lilli
Khorenko, Mikhail
Alves, Frauke
Goldmann, Oliver
Napp, Joanna
Schepers, Ute
Reichardt, Holger M.
Feldmann, Claus
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Inorganic‐organic hybrid nanoparticles (IOH‐NPs) with a general composition [ZrO]2+[RDyeOPO3]2−, [Ln]3+n/3[RDye(SO3)n]n−, [Ln(OH)]2+n/2[RDye(SO3)n]n−, or [LnO]+n[RDye(SO3)n]n− (Ln: lanthanide) are a novel class of nanomaterials for fluorescence detection and optical imaging. IOH‐NPs are characterized by an extremely high load of the fluorescent dye (70–85 wt‐%), high photochemical stability, straightforward aqueous synthesis, low material complexity, intense emission and high cell uptake at low toxicity. Besides full‐color emission, IOH‐NPs are suitable for multimodal imaging, singlet‐oxygen generation as well as drug delivery and drug release. This focus review presents the material concept of the IOH‐NPs as well as their synthesis and characterization. Their characteristic features are illustrated by selected in vitro and in vivo studies to initiate application in biology and medicine.
2018-11-21T14:17:19Z
2018-11-21T14:17:19Z
Article
2199692X
10.1002/cnma.201800310
http://hdl.handle.net/10033/621577
http://doi.wiley.com/10.1002/cnma.201800310
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
ChemNanoMat
oai:repository.helmholtz-hzi.de:10033/6215902019-08-30T11:29:44Zcom_10033_620626com_10033_620601com_10033_620618col_10033_620629col_10033_620603col_10033_620621
2018-11-28T10:27:41Z
urn:hdl:10033/621590
An Interferon Signature Discriminates Pneumococcal From Staphylococcal Pneumonia.
Strehlitz, Anja
Goldmann, Oliver
Pils, Marina C
Pessler, Frank
Medina, Eva
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Staphylococcus aureus
Streptococcus pneumoniae
biomarkers
interferon
pneumonia
transcriptome
Streptococcus pneumoniae is the most common cause of community-acquired pneumonia (CAP). Despite the low prevalence of CAP caused by methicillin-resistant Staphylococcus aureus (MRSA), CAP patients often receive empirical antibiotic therapy providing coverage for MRSA such as vancomycin or linezolid. An early differentiation between S. pneumoniae and S. aureus pneumonia can help to reduce the use of unnecessary antibiotics. The objective of this study was to identify candidate biomarkers that can discriminate pneumococcal from staphylococcal pneumonia. A genome-wide transcriptional analysis of lung and peripheral blood performed in murine models of S. pneumoniae and S. aureus lung infection identified an interferon signature specifically associated with S. pneumoniae infection. Prediction models built using a support vector machine and Monte Carlo cross-validation, identified the combination of the interferon-induced chemokines CXCL9 and CXCL10 serum concentrations as the set of biomarkers with best sensitivity, specificity, and predictive power that enabled an accurate discrimination between S. pneumoniae and S. aureus pneumonia. The predictive performance of these biomarkers was further validated in an independent cohort of mice. This study highlights the potential of serum CXCL9 and CXCL10 biomarkers as an adjunctive diagnostic tool that could facilitate prompt and correct pathogen-targeted therapy in CAP patients.
2018-11-28T10:27:41Z
2018-11-28T10:27:41Z
2018-01-01
Article
1664-3224
29988532
10.3389/fimmu.2018.01424
http://hdl.handle.net/10033/621590
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Frontiers
Frontiers in immunology
oai:repository.helmholtz-hzi.de:10033/6216002019-08-30T11:30:27Zcom_10033_620618col_10033_620619col_10033_620621
2018-12-04T12:53:14Z
urn:hdl:10033/621600
Mast cells as protectors of health.
Dudeck, Anne
Köberle, Martin
Goldmann, Oliver
Meyer, Nicole
Dudeck, Jan
Lemmens, Stefanie
Rohde, M
Roldán, Nestor González
Dietze-Schwonberg, Kirsten
Orinska, Zane
Medina, Eva
Hendrix, Sven
Metz, Martin
Zenclussen, Ana Claudia
von Stebut, Esther
Biedermann, Tilo
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; HIPS, Helmholtz-Institut füt Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
CNS trauma
infection
innate immunity
mast cell
mast cell protease
pregnancy
toxin
tumor
venom
Mast cells (MC), well known for their effector functions in Th2 skewed allergic and also autoimmune inflammation, become increasingly acknowledged for their role in protection of health. It is now clear that they are also key modulators of immune responses at interface organs like skin or gut. MC can prime tissues for adequate inflammatory responses and cooperate with dendritic cells in T cell activation. They also regulate harmful immune responses in trauma and help to successfully orchestrate pregnancy. This review focusses on the beneficial effects of mast cells on tissue homeostasis and elimination of toxins or venoms. MC can enhance pathogen clearance in many bacterial, viral, and parasite infections, e.g. by TLR2 triggered degranulation, secretion of antimicrobial cathelicidins, recruiting neutrophils or by providing extracellular DNA traps. The role of MC in tumors is more ambiguous, however, encouraging new findings show they can change the tumor microenvironment towards anti-tumor immunity when adequately triggered. Uterine tissue remodeling by α-chymase (MCP-5) is crucial for successful embryo implantation. MCP-4 and the tryptase MCP-6 emerge to be protective in CNS trauma by reducing inflammatory damage and excessive scar formation, thereby protecting axon growth. Last but not least, we see proteases like carboxypeptidase A released by FcεRI activated MC detoxify an increasing number of venoms and endogenous toxins. A better understanding of the plasticity of MC will help to improve these advantageous effects, and hint on ways to cut down detrimental MC actions.
2018-12-04T12:53:14Z
2018-12-04T12:53:14Z
2018-11-20
Article
1097-6825
30468774
10.1016/j.jaci.2018.10.054
http://hdl.handle.net/10033/621600
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier
The Journal of allergy and clinical immunology
oai:repository.helmholtz-hzi.de:10033/6216602019-08-30T11:34:19Zcom_10033_620618col_10033_620621
2019-01-18T12:50:52Z
urn:hdl:10033/621660
Disruption of Coronin 1 Signaling in T Cells Promotes Allograft Tolerance while Maintaining Anti-Pathogen Immunity.
Jayachandran, Rajesh
Gumienny, Aleksandra
Bolinger, Beatrice
Ruehl, Sebastian
Lang, Mathias Jakob
Fucile, Geoffrey
Mazumder, Saumyabrata
Tchang, Vincent
Woischnig, Anne-Kathrin
Stiess, Michael
Kunz, Gabriele
Claudi, Beatrice
Schmaler, Mathias
Siegmund, Kerstin
Li, Jianping
Dertschnig, Simone
Holländer, George
Medina, Eva
Karrer, Urs
Moshous, Despina
Bumann, Dirk
Khanna, Nina
Rossi, Simona W
Pieters, Jean
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
The ability of the immune system to discriminate self from non-self is essential for eradicating microbial pathogens but is also responsible for allograft rejection. Whether it is possible to selectively suppress alloresponses while maintaining anti-pathogen immunity remains unknown. We found that mice deficient in coronin 1, a regulator of naive T cell homeostasis, fully retained allografts while maintaining T cell-specific responses against microbial pathogens. Mechanistically, coronin 1-deficiency increased cyclic adenosine monophosphate (cAMP) concentrations to suppress allo-specific T cell responses. Costimulation induced on microbe-infected antigen presenting cells was able to overcome cAMP-mediated immunosuppression to maintain anti-pathogen immunity. In vivo pharmacological modulation of this pathway or a prior transfer of coronin 1-deficient T cells actively suppressed allograft rejection. These results define a coronin 1-dependent regulatory axis in T cells important for allograft rejection and suggest that modulation of this pathway may be a promising approach to achieve long-term acceptance of mismatched allografts.
2019-01-18T12:50:52Z
2019-01-18T12:50:52Z
2019-01-15
Article
Immunity. 2019 Jan 15;50(1):152-165.e8. doi: 10.1016/j.immuni.2018.12.011. Epub 2019 Jan 2.
1097-4180
30611611
10.1016/j.immuni.2018.12.011
http://hdl.handle.net/10033/621660
Immunity
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier (Cell Press)
Immunity
oai:repository.helmholtz-hzi.de:10033/6218062019-08-30T11:28:19Zcom_10033_620591com_10033_128109com_10033_620618col_10033_621771col_10033_620599col_10033_620621
2019-06-07T12:34:07Z
urn:hdl:10033/621806
Longitudinal proliferation mapping in vivo reveals NADPH oxidase-mediated dampening of Staphylococcus aureus growth rates within neutrophils.
Seiß, Elena A
Krone, Anna
Formaglio, Pauline
Goldmann, Oliver
Engelmann, Susanne
Schraven, Burkhart
Medina, Eva
Müller, Andreas J
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Upon the onset of inflammatory responses, bacterial pathogens are confronted with altered tissue microenvironments which can critically impact on their metabolic activity and growth. Changes in these parameters have however remained difficult to analyze over time, which would be critical to dissect the interplay between the host immune response and pathogen physiology. Here, we established an in vivo biosensor for measuring the growth rates of Staphylococcus aureus (S. aureus) on a single cell-level over days in an ongoing cutaneous infection. Using intravital 2-photon imaging and quantitative fluorescence microscopy, we show that upon neutrophil recruitment to the infection site and bacterial uptake, non-lethal dampening of S. aureus proliferation occurred. This inhibition was supported by NADPH oxidase activity. Therefore, reactive oxygen production contributes to pathogen containment within neutrophils not only by killing S. aureus, but also by restricting the growth rate of the bacterium.
2019-06-07T12:34:07Z
2019-06-07T12:34:07Z
2019-04-05
Article
Sci Rep. 2019 Apr 5;9(1):5703. doi: 10.1038/s41598-019-42129-6.
2045-2322
30952906
10.1038/s41598-019-42129-6
http://hdl.handle.net/10033/621806
Scientific Reports
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Nature publishing group
Scientific reports
oai:repository.helmholtz-hzi.de:10033/6218812019-08-30T11:26:40Zcom_10033_620618col_10033_620621
2019-07-17T10:36:50Z
urn:hdl:10033/621881
Myeloid-Derived Suppressor Cells in Infection: A General Overview.
Medina, Eva
Hartl, Dominik
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Eo-myeloid-derived suppressor cells
Infections
Monocytic-myeloid-derived suppressor cells
Myeloid-derived suppressor cells
PMN-myeloid-derived suppressor cells
After initial infection, the immune response that serves to restrict the invading pathogen needs to be tightly calibrated in order to avoid collateral immunopathological damage. This calibration is performed by specialized suppressor mechanisms, which are capable of dampening overwhelming or unremitting inflammation in order to prevent tissue damage. Myeloid-derived suppressor cells (MDSC) are emerging as key players in counter-balancing inflammatory responses and pathogenesis during infection. However, some pathogens are able to exploit the suppressive activities of MDSC to favor pathogen persistence and chronic infections. In this article, we review the current knowledge about the importance of MDSC in the context of bacterial, virus, parasites, and fungal infections.
2019-07-17T10:36:50Z
2019-07-17T10:36:50Z
2018-01-01
Article
J Innate Immun. 2018;10(5-6):407-413. doi: 10.1159/000489830. Epub 2018 Jun 26.
1662-8128
29945134
10.1159/000489830
http://hdl.handle.net/10033/621881
Journal of Innate Immunity
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Karger
Journal of innate immunity
oai:repository.helmholtz-hzi.de:10033/6219332019-09-12T01:27:30Zcom_10033_620533com_10033_620618col_10033_621891col_10033_620621
2019-09-11T10:54:51Z
urn:hdl:10033/621933
Molecular profiling of tissue biopsies reveals unique signatures associated with streptococcal necrotizing soft tissue infections
Thänert, Robert
Itzek, Andreas
Hoßmann, Jörn
Hamisch, Domenica
Madsen, Martin Bruun
Hyldegaard, Ole
Skrede, Steinar
Bruun, Trond
Norrby-Teglund, Anna
Medina, Eva
Pieper, Dietmar H.
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy
General Chemistry
Necrotizing soft tissue infections (NSTIs) are devastating infections caused by either a single pathogen, predominantly Streptococcus pyogenes, or by multiple bacterial species. A better understanding of the pathogenic mechanisms underlying these different NSTI types could facilitate faster diagnostic and more effective therapeutic strategies. Here, we integrate microbial community profiling with host and pathogen(s) transcriptional analysis in patient biopsies to dissect the pathophysiology of streptococcal and polymicrobial NSTIs. We observe that the pathogenicity of polymicrobial communities is mediated by synergistic interactions between community members, fueling a cycle of bacterial colonization and inflammatory tissue destruction. In S. pyogenes NSTIs, expression of specialized virulence factors underlies infection pathophysiology. Furthermore, we identify a strong interferon-related response specific to S. pyogenes NSTIs that could be exploited as a potential diagnostic biomarker. Our study provides insights into the pathophysiology of mono- and polymicrobial NSTIs and highlights the potential of host-derived signatures for microbial diagnosis of NSTIs.
2019-09-11T10:54:51Z
2019-09-11T10:54:51Z
2019-08-26
Article
Nat Commun. 2019 Aug 26;10(1):3846. doi: 10.1038/s41467-019-11722-8.
2041-1723
31451691
10.1038/s41467-019-11722-8
http://hdl.handle.net/10033/621933
Nature communications
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Nature
10
1
oai:repository.helmholtz-hzi.de:10033/6219552019-09-21T01:30:02Zcom_10033_620533com_10033_620618col_10033_621891col_10033_620621
2019-09-20T11:45:23Z
urn:hdl:10033/621955
Diversity of Bacteria Exhibiting Bile Acid-inducible 7α-dehydroxylation Genes in the Human Gut.
Vital, Marius
Rud, Tatjana
Rath, Silke
Pieper, Dietmar H
Schlüter, Dirk
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
7α-dehydroxylation
Bile acids
Gut microbiota
Metagenomics
Microbiome
Systems biology
The secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), formed by gut microbiota from primary bile acids via a multi-step 7α-dehydroxylation reaction, have wide-ranging effects on host metabolism and play an important role in health and disease. A few 7α-dehydroxylating strains have been isolated, where bile acid-inducible (bai) genes were organized in a gene cluster and encoded major enzymes involved. However, only little is known on diversity and abundance of intestinal bacteria catalysing DCA/LCA formation in the human gut in situ. In this study, we took the opportunity to screen metagenome-assembled genomes (MAGs) from sequence data of stool samples provided by two recent studies along with newly available gut-derived isolates for the presence of the bai gene cluster. We revealed in total 765 and 620 MAGs encoding the potential to form DCA/LCA that grouped into 21 and 26 metagenomic species, respectively. The majority of MAGs (92.4 and 90.3%) were associated with a Ruminococcaceae clade that still lacks an isolate, whereas less MAGs belonged to Lachnospiraceae along with eight new isolates (n total = 11) that contained the bai genes. Only a few MAGs were linked to Peptostreptococcaceae. Signatures for horizontal transfer of bai genes were observed. This study gives a comprehensive overview of the diversity of bai-exhibiting bacteria in the human gut highlighting the application of metagenomics to unravel potential functions hidden from current isolates. Eventually, isolates of the identified main MAG clade are required in order to prove their capability of 7α-dehydroxylating primary bile acids.
2019-09-20T11:45:23Z
2019-09-20T11:45:23Z
2019-01-01
Article
Comput Struct Biotechnol J. 2019 Jul 26;17:1016-1019. doi: 10.1016/j.csbj.2019.07.012. eCollection 2019.
2001-0370
31428294
10.1016/j.csbj.2019.07.012
http://hdl.handle.net/10033/621955
Computational and Structural Biotechnology Journal
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier
Computational and structural biotechnology journal
oai:repository.helmholtz-hzi.de:10033/6223672020-07-28T01:25:47Zcom_10033_620618col_10033_620621
2020-07-27T13:23:54Z
urn:hdl:10033/622367
Disruption of Coronin 1 Signaling in T Cells Promotes Allograft Tolerance while Maintaining Anti-Pathogen Immunity.
Jayachandran, Rajesh
Gumienny, Aleksandra
Bolinger, Beatrice
Ruehl, Sebastian
Lang, Mathias Jakob
Fucile, Geoffrey
Mazumder, Saumyabrata
Tchang, Vincent
Woischnig, Anne-Kathrin
Stiess, Michael
Kunz, Gabriele
Claudi, Beatrice
Schmaler, Mathias
Siegmund, Kerstin
Li, Jianping
Dertschnig, Simone
Holländer, George
Medina, Eva
Karrer, Urs
Moshous, Despina
Bumann, Dirk
Khanna, Nina
Rossi, Simona W
Pieters, Jean
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
The ability of the immune system to discriminate self from non-self is essential for eradicating microbial pathogens but is also responsible for allograft rejection. Whether it is possible to selectively suppress alloresponses while maintaining anti-pathogen immunity remains unknown. We found that mice deficient in coronin 1, a regulator of naive T cell homeostasis, fully retained allografts while maintaining T cell-specific responses against microbial pathogens. Mechanistically, coronin 1-deficiency increased cyclic adenosine monophosphate (cAMP) concentrations to suppress allo-specific T cell responses. Costimulation induced on microbe-infected antigen presenting cells was able to overcome cAMP-mediated immunosuppression to maintain anti-pathogen immunity. In vivo pharmacological modulation of this pathway or a prior transfer of coronin 1-deficient T cells actively suppressed allograft rejection. These results define a coronin 1-dependent regulatory axis in T cells important for allograft rejection and suggest that modulation of this pathway may be a promising approach to achieve long-term acceptance of mismatched allografts.
2020-07-27T13:23:54Z
2020-07-27T13:23:54Z
2019-01-02
Article
Other
Immunity. 2019;50(1):152-165.e8. doi:10.1016/j.immuni.2018.12.011.
30611611
10.1016/j.immuni.2018.12.011
http://hdl.handle.net/10033/622367
1097-4180
Immunity
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Elsevier (Cell Press)
50
1
152
165.e8
Immunity
United States
oai:repository.helmholtz-hzi.de:10033/6224032020-08-13T02:57:00Zcom_10033_620618col_10033_620621
2020-08-12T13:18:06Z
urn:hdl:10033/622403
The Natural Product Elegaphenone Potentiates Antibiotic Effects against Pseudomonas aeruginosa.
Zhao, Weining
Cross, Ashley R
Crowe-McAuliffe, Caillan
Weigert-Munoz, Angela
Csatary, Erika E
Solinski, Amy E
Krysiak, Joanna
Goldberg, Joanna B
Wilson, Daniel N
Medina, Eva
Wuest, William M
Sieber, Stephan A
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Pseudomonas aeruginosa
antibiotics
chemical proteomics
natural products
virulence
Natural products represent a rich source of antibiotics that address versatile cellular targets. The deconvolution of their targets via chemical proteomics is often challenged by the introduction of large photocrosslinkers. Here we applied elegaphenone, a largely uncharacterized natural product antibiotic bearing a native benzophenone core scaffold, for affinity-based protein profiling (AfBPP) in Gram-positive and Gram-negative bacteria. This study utilizes the alkynylated natural product scaffold as a probe to uncover intriguing biological interactions with the transcriptional regulator AlgP. Furthermore, proteome profiling of a Pseudomonas aeruginosa AlgP transposon mutant provided unique insights into the mode of action. Elegaphenone enhanced the elimination of intracellular P. aeruginosa in macrophages exposed to sub-inhibitory concentrations of the fluoroquinolone antibiotic norfloxacin.
2020-08-12T13:18:06Z
2020-08-12T13:18:06Z
2019-05-16
Article
Other
Angew Chem Int Ed Engl. 2019;58(25):8581-8584. doi:10.1002/anie.201903472.
30969469
10.1002/anie.201903472
http://hdl.handle.net/10033/622403
1521-3773
Angewandte Chemie (International ed. in English)
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Wiley-VCH
58
25
8581
8584
Angewandte Chemie (International ed. in English)
United States
United States
United States
International
Germany
oai:repository.helmholtz-hzi.de:10033/6224332020-09-28T10:51:11Zcom_10033_128109com_10033_620659com_10033_6839com_10033_620618col_10033_128110col_10033_620660col_10033_621495col_10033_620621
2020-09-10T07:20:07Z
urn:hdl:10033/622433
Staphylococcus aureus Alpha-Toxin Limits Type 1 While Fostering Type 3 Immune Responses.
Bonifacius, Agnes
Goldmann, Oliver
Floess, Stefan
Holtfreter, Silva
Robert, Philippe A
Nordengrün, Maria
Kruse, Friederike
Lochner, Matthias
Falk, Christine S
Schmitz, Ingo
Bröker, Barbara M
Medina, Eva
Huehn, Jochen
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
CD4+ T cells
Staphylococcus aureus
alpha-toxin
innate lymphoid cells
γδ T cells
Staphylococcus aureus can cause life-threatening diseases, and hospital- as well as community-associated antibiotic-resistant strains are an emerging global public health problem. Therefore, prophylactic vaccines or immune-based therapies are considered as alternative treatment opportunities. To develop such novel treatment approaches, a better understanding of the bacterial virulence and immune evasion mechanisms and their potential effects on immune-based therapies is essential. One important staphylococcal virulence factor is alpha-toxin, which is able to disrupt the epithelial barrier in order to establish infection. In addition, alpha-toxin has been reported to modulate other cell types including immune cells. Since CD4+ T cell-mediated immunity is required for protection against S. aureus infection, we were interested in the ability of alpha-toxin to directly modulate CD4+ T cells. To address this, murine naïve CD4+ T cells were differentiated in vitro into effector T cell subsets in the presence of alpha-toxin. Interestingly, alpha-toxin induced death of Th1-polarized cells, while cells polarized under Th17 conditions showed a high resistance toward increasing concentrations of this toxin. These effects could neither be explained by differential expression of the cellular alpha-toxin receptor ADAM10 nor by differential activation of caspases, but might result from an increased susceptibility of Th1 cells toward Ca2+-mediated activation-induced cell death. In accordance with the in vitro findings, an alpha-toxin-dependent decrease of Th1 and concomitant increase of Th17 cells was observed in vivo during S. aureus bacteremia. Interestingly, corresponding subsets of innate lymphoid cells and γδ T cells were similarly affected, suggesting a more general effect of alpha-toxin on the modulation of type 1 and type 3 immune responses. In conclusion, we have identified a novel alpha-toxin-dependent immunomodulatory strategy of S. aureus, which can directly act on CD4+ T cells and might be exploited for the development of novel immune-based therapeutic approaches to treat infections with antibiotic-resistant S. aureus strains.
2020-09-10T07:20:07Z
2020-09-10T07:20:07Z
2020-08-07
Article
Front Immunol. 2020;11:1579. Published 2020 Aug 7. doi:10.3389/fimmu.2020.01579.
32849537
10.3389/fimmu.2020.01579
http://hdl.handle.net/10033/622433
1664-3224
Frontiers in immunology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Frontiers
11
1579
Frontiers in immunology
Switzerland
oai:repository.helmholtz-hzi.de:10033/6224352020-09-11T04:23:37Zcom_10033_620618com_10033_620968col_10033_620969col_10033_620621
2020-09-10T08:38:13Z
urn:hdl:10033/622435
Identification of a Novel LysR-Type Transcriptional Regulator in Staphylococcus aureus That Is Crucial for Secondary Tissue Colonization during Metastatic Bloodstream Infection.
Groma, Michaela
Horst, Sarah A
Das, Sudip
Huettel, Bruno
Klepsch, Maximilian
Rudel, Thomas
Medina, Eva
Fraunholz, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Staphylococcus aureus
metabolic adaptation
secondary site infection
transcriptional regulation
Staphylococcus aureus is a common cause of bacteremia that can lead to severe complications once the bacteria exit the bloodstream and establish infection in secondary organs. Despite its clinical relevance, little is known about the bacterial factors facilitating the development of these metastatic infections. Here, we used an S. aureus transposon mutant library coupled to transposon insertion sequencing (Tn-Seq) to identify genes that are critical for efficient bacterial colonization of secondary organs in a murine model of metastatic bloodstream infection. Our transposon screen identified a LysR-type transcriptional regulator (LTTR), which was required for efficient colonization of secondary organs such as the kidneys in infected mice. The critical role of LTTR in secondary organ colonization was confirmed using an isogenic mutant deficient in the expression of LTTR. To identify the set of genes controlled by LTTR, we used an S. aureus strain carrying the LTTR gene in an inducible expression plasmid. Gene expression analysis upon induction of LTTR showed increased transcription of genes involved in branched-chain amino acid biosynthesis, a methionine sulfoxide reductase, and a copper transporter as well as decreased transcription of genes coding for urease and components of pyrimidine nucleotides. Furthermore, we show that transcription of LTTR is repressed by glucose, is induced under microaerobic conditions, and required trace amounts of copper ions. Our data thus pinpoints LTTR as an important element that enables a rapid adaptation of S. aureus to the changing host microenvironment.IMPORTANCEStaphylococcus aureus is an important pathogen that can disseminate via the bloodstream and establish metastatic infections in distant organs. To achieve a better understanding of the bacterial factors facilitating the development of these metastatic infections, we used in this study a Staphylococcus aureus transposon mutant library in a murine model of intravenous infection, where bacteria first colonize the liver as the primary infection site and subsequently progress to secondary sites such as the kidney and bones. We identified a novel LysR-type transcriptional regulator (LTTR), which was specifically required by S. aureus for efficient colonization of secondary organs. We also determined the transcriptional activation as well as the regulon of LTTR, which suggests that this regulator is involved in the metabolic adaptation of S. aureus to the host microenvironment found in secondary infection sites.
2020-09-10T08:38:13Z
2020-09-10T08:38:13Z
2020-08-25
Article
mBio. 2020;11(4):e01646-20. Published 2020 Aug 25.
32843554
10.1128/mBio.01646-20
http://hdl.handle.net/10033/622435
2150-7511
mBio
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
ASM
11
4
mBio
United States
oai:repository.helmholtz-hzi.de:10033/6231302022-01-08T01:49:20Zcom_10033_620618com_10033_620636com_10033_620968col_10033_620970col_10033_620638col_10033_620621
2022-01-07T10:16:18Z
urn:hdl:10033/623130
Dysregulated Immunometabolism Is Associated with the Generation of Myeloid-Derived Suppressor Cells in Staphylococcus aureus Chronic Infection.
Dietrich, Oliver
Heinz, Alexander
Goldmann, Oliver
Geffers, Robert
Beineke, Andreas
Hiller, Karsten
Saliba, Antoine-Emmanuel
Medina, Eva
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Immunometabolism
Myeloid-derived suppressor cells
Single-cell RNA sequencing
Staphylococcus aureus
Myeloid-derived suppressor cells (MDSCs) are a compendium of immature myeloid cells that exhibit potent T-cell suppressive capacity and expand during pathological conditions such as cancer and chronic infections. Although well-characterized in cancer, the physiology of MDSCs in the infection setting remains enigmatic. Here, we integrated single-cell RNA sequencing (scRNA-seq) and functional metabolic profiling to gain deeper insights into the factors governing the generation and maintenance of MDSCs in chronic Staphylococcus aureus infection. We found that MDSCs originate not only in the bone marrow but also at extramedullary sites in S. aureus-infected mice. scRNA-seq showed that infection-driven MDSCs encompass a spectrum of myeloid precursors in different stages of differentiation, ranging from promyelocytes to mature neutrophils. Furthermore, the scRNA-seq analysis has also uncovered valuable phenotypic markers to distinguish mature myeloid cells from immature MDSCs. Metabolic profiling indicates that MDSCs exhibit high glycolytic activity and high glucose consumption rates, which are required for undergoing terminal maturation. However, rapid glucose consumption by MDSCs added to infection-induced perturbations in the glucose supplies in infected mice hinders the terminal maturation of MDSCs and promotes their accumulation in an immature stage. In a proof-of-concept in vivo experiment, we demonstrate the beneficial effect of increasing glucose availability in promoting MDSC terminal differentiation in infected mice. Our results provide valuable information of how metabolic alterations induced by infection influence reprogramming and differentiation of MDSCs.
2022-01-07T10:16:18Z
2022-01-07T10:16:18Z
2021-11-11
Article
J Innate Immun. 2021 Nov 11:1-18. doi: 10.1159/000519306. Epub ahead of print.
34763332
10.1159/000519306
http://hdl.handle.net/10033/623130
1662-8128
Journal of innate immunity
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Karger
1
18
Journal of innate immunity
Switzerland