Oliver Kurzai

Publications

• 3.81

  Impact points

  The Arthroderma benhamiae hydrophobin HypA mediates hydrophobicity and influences recognition by human immune effector cells.

  Christoph Heddergott, Sandra Bruns, Sandor Nietzsche, Ines Leonhardt, Oliver Kurzai, Olaf Kniemeyer, Axel A Brakhage

  Eukaryotic cell. 03/2012;

  Dermatophytes are the most common cause of superficial mycoses in humans and animals. They can co-exist with their hosts for many years without causing significant symptoms but also cause highly inflammatory infection. To identify mechanisms involved in the modulation of the host response during inf... [more] Dermatophytes are the most common cause of superficial mycoses in humans and animals. They can co-exist with their hosts for many years without causing significant symptoms but also cause highly inflammatory infection. To identify mechanisms involved in the modulation of the host response during infection caused by the zoophilic dermatophyte Arthroderma benhamiae, cell wall-associated surface proteins were studied. By 2-dimensional gel electrophoresis we found that a hydrophobin protein designated HypA was the dominant cell surface protein. HypA was also detected in the supernatant during growth and conidiation of the fungus. The A. benhamiae genome only encodes a single hydrophobin gene designated hypA. A hypA deletion mutant was generated as well as a complemented hypA mutant strain, hypA(C). In contrast to the wild type and the complemented strain, the hypA deletion mutant exhibited 'easily wetable' mycelia and conidia indicating the loss of surface hydrophobicity of both morphotypes. Compared with the wild type, the hypA deletion mutant triggered an increased activation of human neutrophil granulocytes and dendritic cells characterised by an increased release of the immune mediators interleukin (IL) 6, IL-8, IL-10, TNF-α. For the first time, we observed the formation of neutrophil extracellular traps against dermatophytes, whose formation was inreased by the ΔhypA mutant compared with the wt. Furthermore, conidia of the ΔhypA strain were killed more effectively by neutrophils. Our data suggest that recognition of A. benhamiae by the cellular immune defence system is notably influenced by the presence of the surface rodlet layer formed by the hydrophobin HypA.
• 1.32

  Impact points

  40-O -[2-Hydroxyethyl]rapamycin modulates human dendritic cell function during exposure to Aspergillus fumigatus.

  Ruth Bauer, Markus Mezger, Christian Blockhaus, Anna-Lena Schmitt, Oliver Kurzai, Hermann Einsele, Juergen Loeffler

  Journal of basic microbiology. 07/2011;

  40-O -[2-Hydroxyethyl]rapamycin (RAD), a novel derivative of the immunosuppressive drug rapamycin, was analyzed for its immunomodulatory influence during the interaction of human monocyte-derived dendritic cells (moDC) with Aspergillus fumigatus. RAD is clinically used to prevent graft-versus -host ... [more] 40-O -[2-Hydroxyethyl]rapamycin (RAD), a novel derivative of the immunosuppressive drug rapamycin, was analyzed for its immunomodulatory influence during the interaction of human monocyte-derived dendritic cells (moDC) with Aspergillus fumigatus. RAD is clinically used to prevent graft-versus -host disease as well as solid organ and bone marrow transplant rejection. However, it may constitute a risk factor for the development of opportunistic infections, such as invasive aspergillosis which is mainly caused by the most common airborne fungal pathogen A. fumigatus. moDC were generated in the presence or absence of RAD. In this setting, RAD had various modulating effects on the immune function of DC. A decrease of pro- and anti-inflammatory cytokines (IL-12, TNF-α, CCL20, IL-10) was observed. Furthermore, RAD reduced the expression of innate immunity receptors (TLR2, TLR4, dectin-1), impaired the maturation capacity of moDC observed through the reduction of costimulatory factors (CD40, CD80, CD83, CD86), and impaired their capacity to phagocytose and damage A. fumigatus. These data demonstrate that RAD influences the differentiation of DC. RAD modulates the cytokine response of DC to A. fumigatus and reduces their ability to kill germ tubes. Thus, RAD treatment might affect the risk of invasive aspergillosis independently of its capacity of blocking T cell activation. (© 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim).
• 5.65

  Impact points

  Human NK cells display important antifungal activity against Aspergillus fumigatus, which is directly mediated by IFN-γ release.

  Maria Bouzani, Michael Ok, Allison McCormick, Frank Ebel, Oliver Kurzai, C Oliver Morton, Hermann Einsele, Juergen Loeffler

  Journal of immunology (Baltimore, Md. : 1950). 06/2011; 187(3):1369-76.

  Despite the strong interest in the NK cell-mediated immunity toward malignant cells and viruses, there is a relative lack of data on the interplay between NK cells and filamentous fungi, especially Aspergillus fumigatus, which is the major cause of invasive aspergillosis. By studying the in vitro in... [more] Despite the strong interest in the NK cell-mediated immunity toward malignant cells and viruses, there is a relative lack of data on the interplay between NK cells and filamentous fungi, especially Aspergillus fumigatus, which is the major cause of invasive aspergillosis. By studying the in vitro interaction between human NK cells and A. fumigatus, we found only germinated morphologies to be highly immunogenic, able to induce a Th1-like response, and capable of upregulating cytokines such as IFN-γ and TNF-α. Moreover, priming NK cells with human rIL-2 and stimulating NK cells by direct NK cell-pathogen contact were essential to induce damage against A. fumigatus. However, the most interesting finding was that NK cells did not mediate anti-Aspergillus cytotoxicity through degranulation of their cytotoxic proteins (perforin, granzymes, granulysine), but via an alternative mechanism involving soluble factor(s). To our knowledge, our study is the first to demonstrate that IFN-γ, released by NK cells, directly damages A. fumigatus, attributing new properties to both human NK cells and IFN-γ and suggesting them as possible therapeutic tools against IA.
• 1.40

  Impact points

  [Ulcerating nodules on the right arm after hunting muskrats].

  Andreas Kerstan, Ana-M Wendel, Oliver Kurzai, Eva-B Bröcker, Annette Kolb-Mäurer

  Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 06/2011; 9(6):487-9.
• 5.33

  Impact points

  Neisseria meningitidis adhesin NadA targets beta1 integrins: functional similarity to Yersinia invasin.

  Virginie Nägele, Jürgen Heesemann, Stephanie Schielke, Luisa F Jiménez-Soto, Oliver Kurzai, Nikolaus Ackermann

  The Journal of biological chemistry. 04/2011; 286(23):20536-46.

  Meningococci are facultative-pathogenic bacteria endowed with a set of adhesins allowing colonization of the human upper respiratory tract, leading to fulminant meningitis and septicemia. The Neisseria adhesin NadA was identified in about 50% of N. meningitidis isolates and is closely related to the... [more] Meningococci are facultative-pathogenic bacteria endowed with a set of adhesins allowing colonization of the human upper respiratory tract, leading to fulminant meningitis and septicemia. The Neisseria adhesin NadA was identified in about 50% of N. meningitidis isolates and is closely related to the Yersinia adhesin YadA, the prototype of the oligomeric coiled-coil adhesin (Oca) family. NadA is known to be involved in cell adhesion, invasion, and induction of proinflammatory cytokines. Because of the enormous diversity of neisserial cell adhesins the analysis of the specific contribution of NadA in meningococcal host interactions is limited. Therefore, we used a non-invasive Y. enterocolitica mutant as carrier to study the role of NadA in host cell interaction. NadA was shown to be efficiently produced and localized in its oligomeric form on the bacterial surface of Y. enterocolitica. Additionally, NadA mediated a β1 integrin-dependent adherence with subsequent internalization of yersiniae by a β1 integrin-positive cell line. Using recombinant NadA(24-210) protein and human and murine β1 integrin-expressing cell lines we could demonstrate the role of the β1 integrin subunit as putative receptor for NadA. Subsequent inhibition assays revealed specific interaction of NadA(24-210) with the human β1 integrin subunit. Cumulatively, these results indicate that Y. enterocolitica is a suitable toolbox system for analysis of the adhesive properties of NadA, revealing strong evidence that β1 integrins are important receptors for NadA. Thus, this study demonstrated for the first time a direct interaction between the Oca-family member NadA and human β1 integrins.
• 2.27

  Impact points

  Real-time PCR and quantitative culture for monitoring of experimental Aspergillus fumigatus intracranial infection in neutropenic mice.

  C Oliver Morton, Karl V Clemons, Jan Springer, Justus G Mueller, Thomas R Rogers, David A Stevens, Oliver Kurzai, Hermann Einsele, Juergen Loeffler

  Journal of medical microbiology. 03/2011; 60(Pt 7):913-9.

  The central nervous system (CNS) is the most common site of dissemination during Aspergillus infection. PCR has the potential to facilitate early diagnosis of CNS aspergillosis, which could assist in reducing disease mortality. In two experiments, neutropenic CD-1 male mice were infected intracrania... [more] The central nervous system (CNS) is the most common site of dissemination during Aspergillus infection. PCR has the potential to facilitate early diagnosis of CNS aspergillosis, which could assist in reducing disease mortality. In two experiments, neutropenic CD-1 male mice were infected intracranially with 5×10⁶ conidia of Aspergillus fumigatus. At time points up to 120 h after infection, mice were euthanized and samples of blood, brain, spinal cord and cerebrospinal fluid (CSF) were taken. The brain fungal burden was determined by quantitative culture, and fungal DNA was detected by quantitative PCR. Plating for A. fumigatus from the brain confirmed that all mice had burdens of log₁₀>3 from 4 to 120 h after infection. A. fumigatus DNA was detected in blood (88 %), brain (96 %), CSF (52 %) and spinal cord (92 %) samples. The brain and spinal cord contained the highest concentrations of fungal DNA. Adapting the extraction protocol to maximize yield from small sample volumes (10 µl CSF or 200 µl blood) allowed PCR detection of A. fumigatus in infected mice, suggesting the use of CSF and blood as diagnostic clinical samples for CNS aspergillosis.
• 2.06

  Impact points

  Endophthalmitis as primary clinical manifestation of fatal fusariosis in an allogeneic stem cell recipient.

  M Kapp, M Schargus, T Deuchert, J Springer, F Wendel, J Loeffler, G U Grigoleit, O Kurzai, W Heinz, H Einsele, G Stuhler

  Transplant infectious disease : an official journal of the Transplantation Society. 02/2011; 13(4):374-9.

  The occurrence of infections due to previously rare opportunistic pathogens is increasing despite the use of novel treatment strategies for immunocompromised patients. Here, we report the case of a patient presenting with fever, muscle pain, and bilateral endophthalmitis after allogeneic hematopoiet... [more] The occurrence of infections due to previously rare opportunistic pathogens is increasing despite the use of novel treatment strategies for immunocompromised patients. Here, we report the case of a patient presenting with fever, muscle pain, and bilateral endophthalmitis after allogeneic hematopoietic stem cell transplantation. Fusarium solani was isolated from peripheral blood samples and identified as the cause of gradual bilateral vision loss, despite appropriate antifungal prophylaxis, and therapy including vitrectomy and intraocular instillation of antifungal agents. The patient became comatose; basal meningitis involving both optic nerves was suspected based on magnetic resonance tomography. The patient died 8 days later due to septic multi-organ failure. Autopsy revealed that both kidneys, but no other organs, were infiltrated by Fusarium. No fungus was found in cerebral tissues or cerebrospinal fluid. Our case demonstrates some of the typical clinical features of systemic fusariosis and its potentially fatal outcome. The clinical observations reported here may help clinicians caring for immunocompromised patients to accelerate diagnosis and initiate treatment early at the onset of this fatal complication, and highlight the urgent need for interdisciplinary management of invasive fusariosis.
• 2.80

  Impact points

  Characterization of FarR as a highly specialized, growth phase-dependent transcriptional regulator in Neisseria meningitidis.

  Stephanie Schielke, Carolin Spatz, Roland Felix Schwarz, Biju Joseph, Christoph Schoen, Sabine Marita Schulz, Kerstin Hubert, Matthias Frosch, Alexandra Schubert-Unkmeir, Oliver Kurzai

  International journal of medical microbiology : IJMM. 02/2011; 301(4):325-33.

  Transcriptional regulators play an important role for the survival of Neisseria meningitidis within its human host. We have recently shown that FarR acts as transcriptional repressor of the adhesin nadA in N. meningitidis. Here, we examined the FarR regulon by microarray analyses, qRT-PCR, and elect... [more] Transcriptional regulators play an important role for the survival of Neisseria meningitidis within its human host. We have recently shown that FarR acts as transcriptional repressor of the adhesin nadA in N. meningitidis. Here, we examined the FarR regulon by microarray analyses, qRT-PCR, and electrophoretic mobility shift assays, revealing that FarR is a highly specific repressor of nadA. We demonstrate by reporter gene fusion assays that alterations of the FarR binding site within the nadA promoter are sufficient to induce transcription of nadA. Furthermore, farR expression is growth phase-dependent. The highest transcription rate was observed in the late-exponential growth phase of meningococci. Upon contact with active components of the complement system in normal human serum, expression of farR is slightly downregulated. Concluding, we present FarR as an exquisitely specialized, growth phase-dependent, possibly complement-responsive transcriptional regulator in N. meningitidis.
• 4.41

  Impact points

  The temporal dynamics of differential gene expression in Aspergillus fumigatus interacting with human immature dendritic cells in vitro.

  Charles O Morton, John J Varga, Anke Hornbach, Markus Mezger, Helga Sennefelder, Susanne Kneitz, Oliver Kurzai, Sven Krappmann, Hermann Einsele, William C Nierman, Thomas R Rogers, Juergen Loeffler

  PloS one. 01/2011; 6(1):e16016.

  Dendritic cells (DC) are the most important antigen presenting cells and play a pivotal role in host immunity to infectious agents by acting as a bridge between the innate and adaptive immune systems. Monocyte-derived immature DCs (iDC) were infected with viable resting conidia of Aspergillus fumiga... [more] Dendritic cells (DC) are the most important antigen presenting cells and play a pivotal role in host immunity to infectious agents by acting as a bridge between the innate and adaptive immune systems. Monocyte-derived immature DCs (iDC) were infected with viable resting conidia of Aspergillus fumigatus (Af293) for 12 hours at an MOI of 5; cells were sampled every three hours. RNA was extracted from both organisms at each time point and hybridised to microarrays. iDC cell death increased at 6 h in the presence of A. fumigatus which coincided with fungal germ tube emergence; >80% of conidia were associated with iDC. Over the time course A. fumigatus differentially regulated 210 genes, FunCat analysis indicated significant up-regulation of genes involved in fermentation, drug transport, pathogenesis and response to oxidative stress. Genes related to cytotoxicity were differentially regulated but the gliotoxin biosynthesis genes were down regulated over the time course, while Aspf1 was up-regulated at 9 h and 12 h. There was an up-regulation of genes in the subtelomeric regions of the genome as the interaction progressed. The genes up-regulated by iDC in the presence of A. fumigatus indicated that they were producing a pro-inflammatory response which was consistent with previous transcriptome studies of iDC interacting with A. fumigatus germ tubes. This study shows that A. fumigatus adapts to phagocytosis by iDCs by utilising genes that allow it to survive the interaction rather than just up-regulation of specific virulence genes.
• 4.41

  Impact points

  The Candida albicans-specific gene EED1 encodes a key regulator of hyphal extension.

  Ronny Martin, Gary P Moran, Ilse D Jacobsen, Antje Heyken, Jenny Domey, Derek J Sullivan, Oliver Kurzai, Bernhard Hube

  PloS one. 01/2011; 6(4):e18394.

  The extension of germ tubes into elongated hyphae by Candida albicans is essential for damage of host cells. The C. albicans-specific gene EED1 plays a crucial role in this extension and maintenance of filamentous growth. eed1Δ cells failed to extend germ tubes into long filaments and switched back ... [more] The extension of germ tubes into elongated hyphae by Candida albicans is essential for damage of host cells. The C. albicans-specific gene EED1 plays a crucial role in this extension and maintenance of filamentous growth. eed1Δ cells failed to extend germ tubes into long filaments and switched back to yeast growth after 3 h of incubation during growth on plastic surfaces. Expression of EED1 is regulated by the transcription factor Efg1 and ectopic overexpression of EED1 restored filamentation in efg1Δ. Transcriptional profiling of eed1Δ during infection of oral tissue revealed down-regulation of hyphal associated genes including UME6, encoding another key transcriptional factor. Ectopic overexpression of EED1 or UME6 rescued filamentation and damage potential in eed1Δ. Transcriptional profiling during overexpression of UME6 identified subsets of genes regulated by Eed1 or Ume6. These data suggest that Eed1 and Ume6 act in a pathway regulating maintenance of hyphal growth thereby repressing hyphal-to-yeast transition and permitting dissemination of C. albicans within epithelial tissues.
• 1.32

  Impact points

  Medical microbiology.

  Oliver Kurzai, Erika Kothe

  Journal of basic microbiology. 12/2010; 50 Suppl 1:S3.
• 4.16

  Impact points

  Pathogen-specific DNA enrichment does not increase sensitivity of PCR for diagnosis of invasive aspergillosis in neutropenic patients.

  Jan Springer, Juergen Loeffler, Werner Heinz, Hannes Schlossnagel, Marc Lehmann, Oliver Morton, Thomas R Rogers, Corinna Schmitt, Matthias Frosch, Hermann Einsele, Oliver Kurzai

  Journal of clinical microbiology. 12/2010; 49(4):1267-73.

  PCR assays designed for the diagnosis of invasive aspergillosis (IA) in high-risk patients have to detect minute amounts of target DNA to reach sufficient analytical sensitivity to be of clinical use. This prospective study assessed the use of a novel strategy for selective pathogen DNA enrichment f... [more] PCR assays designed for the diagnosis of invasive aspergillosis (IA) in high-risk patients have to detect minute amounts of target DNA to reach sufficient analytical sensitivity to be of clinical use. This prospective study assessed the use of a novel strategy for selective pathogen DNA enrichment for enhancing the performance of diagnostic PCR in a direct comparison with a highly sensitive in-house quantitative PCR (qPCR) assay and the galactomannan enzyme-linked immunosorbent assay (ELISA). Surprisingly, and in contrast to experience with other patient groups, the novel protocol for selective pathogen DNA enrichment did not enhance but instead significantly impaired sensitivity. This could be explained by the small amounts of host DNA in the specimens, which were derived mostly from severely neutropenic patients. In the qPCR assay, positive samples required an average of 43.5 amplification cycles (range, 39.2 to 50) for detection in the in-house PCR. Repetitive testing of selected samples showed test positivity to be variable, most likely due to the small amounts of target DNA. Despite this, the in-house protocol proved helpful in the diagnosis of IA, detecting 2 out of 3 patients with probable IA and 10 out of 19 patients with possible IA. Our results underline the necessity for diagnostic PCR protocols that help diagnose IA to be highly sensitive and show that selective pathogen DNA enrichment using affinity purification may not be useful in severely neutropenic patients.
• 2.13

  Impact points

  Role of glycogen synthase kinase 3 (GSK-3) in innate immune response of human immature dendritic cells to Aspergillus fumigatus.

  Katrin Spinnler, Markus Mezger, Michael Steffens, Helga Sennefelder, Oliver Kurzai, Hermann Einsele, Juergen Loeffler

  Medical mycology : official publication of the International Society for Human and Animal Mycology. 06/2010; 48(4):589-97.

  Dysregulation of the Th1/Th2 cytokine balance and a switch to a Th2 immune response contribute to the development of and the unfavorable outcome from invasive aspergillosis (IA). We explore in this paper the role of glycogen synthase kinase 3 (GSK-3) in human immature dendritic cells (iDCs) relative... [more] Dysregulation of the Th1/Th2 cytokine balance and a switch to a Th2 immune response contribute to the development of and the unfavorable outcome from invasive aspergillosis (IA). We explore in this paper the role of glycogen synthase kinase 3 (GSK-3) in human immature dendritic cells (iDCs) relative to infection caused by A. fumigatus by the use of GSK-3 inhibitors (LiCl, SB415286) and RNA interference technology. In iDCs exposed to A. fumigatus germ tubes, inhibition of GSK-3 with LiCl or SB415286, as well as transfection with small interfering RNA, led to markedly elevated expression of the anti-inflammatory cytokine IL-10. In contrast, pro-inflammatory cytokine response was only partially regulated by GSK-3. Screening of patients after allogeneic stem cell transplantation (with or without IA) for the presence of genetic markers (rs334558, rs6438552) in the GSK-3 gene revealed no significant association with an increased risk for IA. In conclusion, GSK-3 might be involved in the regulation of the anti-inflammatory response of iDCs in the context of infections due to A. fumigatus, albeit the exact mechanisms have to be clarified in future experiments.

• Eradication is impossible.

  Oliver Kurzai

  Deutsches Ärzteblatt international. 05/2010; 107(21):369; author reply 369-70.
• 3.77

  Impact points

  Virulence determinants involved in differential host niche adaptation of Neisseria meningitidis and Neisseria gonorrhoeae.

  Stephanie Schielke, Matthias Frosch, Oliver Kurzai

  Medical microbiology and immunology. 04/2010; 199(3):185-96.

  Neisseria meningitidis and Neisseria gonorrhoeae are the only pathogenic species of the genus Neisseria. Although these two species are closely related, they specialized on survival in completely different environments within the human host-the nasopharynx in the case of N. meningitidis versus the u... [more] Neisseria meningitidis and Neisseria gonorrhoeae are the only pathogenic species of the genus Neisseria. Although these two species are closely related, they specialized on survival in completely different environments within the human host-the nasopharynx in the case of N. meningitidis versus the urogenital tract in the case of N. gonorrhoeae. The genetic background of these differences has not yet been determined. Here, we present a comparison of all characterized transcriptional regulators in these species, delineating analogous functions and disclosing differential functional developments of these DNA-binding proteins with a special focus on the recently characterized regulator FarR and its contribution to divergent host niche adaptation in the two Neisseria spp. Furthermore, we summarize the present knowledge on two-partner secretion systems in meningococci, highlighting their overall expression among meningococcal strains in contrast to the complete absence in gonococci. Concluding, the decisive role of these two entirely different factors in host niche adaptation of the two human pathogenic Neisseria species is depicted, illuminating another piece of the puzzle to locate the molecular basis of their differences in preferred colonization sites and pathogenicity.
• 3.69

  Impact points

  The transcriptional repressor FarR is not involved in meningococcal fatty acid resistance mediated by the FarAB efflux pump and dependent on lipopolysaccharide structure.

  Stephanie Schielke, Corinna Schmitt, Carolin Spatz, Matthias Frosch, Alexandra Schubert-Unkmeir, Oliver Kurzai

  Applied and environmental microbiology. 03/2010; 76(10):3160-9.

  Free fatty acids are important antimicrobial substances regulating the homeostasis of colonizing bacteria on epithelial surfaces. Here, we show that meningococci express a functional farAB efflux pump, which is indispensable for fatty acid resistance. However, other than in Neisseria gonorrhoeae, th... [more] Free fatty acids are important antimicrobial substances regulating the homeostasis of colonizing bacteria on epithelial surfaces. Here, we show that meningococci express a functional farAB efflux pump, which is indispensable for fatty acid resistance. However, other than in Neisseria gonorrhoeae, the transcriptional regulator FarR is not involved in regulation of this operon in Neisseria meningitidis. We tested the susceptibility of 23 meningococcal isolates against saturated and unsaturated long-chain fatty acids, proving that meningococci are generally highly resistant, with the exception of serogroup Y strains belonging to sequence type 23. Using genetically determined lipopolysaccharide (LPS)-truncated mutant strains, we show that addition of the LPS core oligosaccharide and hexa-acylation of its membrane anchor lipid A are imperative for fatty acid resistance of meningococci. The sensitivity of the serogroup Y strains is due to naturally occurring mutations within the lpxL1 gene, which is responsible for addition of the sixth acyl chain on the LPS membrane anchor lipid A. Therefore, fatty acid resistance in meningococci is provided by both the active efflux pump FarAB and by the natural permeability barrier of the Gram-negative outer membrane. The transcriptional regulator FarR is not implicated in fatty acid resistance in meningococci, possibly giving rise to a constitutively active FarAB efflux pump system and thus revealing diverse mechanisms of niche adaptation in the two closely related Neisseria species.
• 8.11

  Impact points

  Comparison of two interferon-gamma release assays and tuberculin skin test for detecting latent tuberculosis in patients with immune-mediated inflammatory diseases.

  S Kleinert, O Kurzai, J Elias, K Marten, C Engelke, M Feuchtenberger, J Sandstede, M Frosch, H-P Tony, C Kneitz

  Annals of the rheumatic diseases. 02/2010; 69(4):782-4.
• 4.21

  Impact points

  The GPI-anchored protease Sap9 modulates the interaction of Candida albicans with human neutrophils.

  Anke Hornbach, Antje Heyken, Lydia Schild, Bernhard Hube, Jürgen Löffler, Oliver Kurzai

  Infection and immunity. 10/2009;

  Human neutrophils (PMNs) play a major role in the immune defence against invasive Candida albicans infection. This fungal pathogen produces a set of aspartic proteases which directly contributes to virulence properties like adhesion, tissue invasion and immune evasion. Here we show that, in contrast... [more] Human neutrophils (PMNs) play a major role in the immune defence against invasive Candida albicans infection. This fungal pathogen produces a set of aspartic proteases which directly contributes to virulence properties like adhesion, tissue invasion and immune evasion. Here we show that, in contrast to other secreted proteases, the cell surface associated isoform Sap9 has a major impact on recognition of Candida albicans by polymorphonuclear neutrophils (PMNs). SAP9 is required for the induction of PMN chemotaxis towards C. albicans filaments, an essential prerequisite of effective PMN activation. Furthermore, deletion of SAP9 leads to a mitigated release of reactive oxygen intermediates (ROI) in human PMNs and decreases C. albicans induced apoptosis triggered by ROI formation. In confrontation assays, killing of a SAP9 deletion mutant is reduced in comparison to wild-type C. albicans. These data clearly implicate Sap9 protease activity with the initiation of protective innate immunity and suggest novel molecular mechanisms in C. albicans - host interaction leading to neutrophil activation.
• 2.37

  Impact points

  Immune Responses of Human Immature Dendritic Cells Can Be Modulated by the Recombinant Aspergillus fumigatus Antigen Aspf1.

  Michael Ok, Jean-Paul Latgé, Carina Baeuerlein, Frank Ebel, Markus Mezger, Max Topp, Oliver Kurzai, Doreen Killian, Markus Kapp, Goetz-Ulrich Grigoleit, Helga Sennefelder, Javier Arroyo, Hermann Einsele, Juergen Loeffler

  Clinical and vaccine immunology : CVI. 09/2009;

  Invasive aspergillosis is a significant cause of morbidity and mortality in patients after stem cells transplantation, in solid organ transplant recipients and patients with haematological malignancies. The interactions between human immature dendritic cells (iDCs) and Aspergillus fumigatus antigens... [more] Invasive aspergillosis is a significant cause of morbidity and mortality in patients after stem cells transplantation, in solid organ transplant recipients and patients with haematological malignancies. The interactions between human immature dendritic cells (iDCs) and Aspergillus fumigatus antigens are widely uncharacterized. We analyzed the immune response of iDCs to different recombinant A. fumigatus antigens (Aspf1 and Crf1). One of these antigens, the 18kDa ribonuclease Aspf1, triggered an increased expression of genes encoding pro-inflammatory cytokines and chemokines, augmented activation of NFkappaB and apoptosis of iDCs. Furthermore, by fluorescence microscopy we could demonstrate that in the first 3 h a major portion of Aspf1 accumulates on the cell surface. Finally, we could show an increased segregation of cytokines and chemokines after stimulation of iDCs by an Aspf1 deletion mutant strain of A. fumigatus.
• 5.36

  Impact points

  Expression of the meningococcal adhesin NadA is controlled by a transcriptional regulator of the MarR-family.

  Stephanie Schielke, Claudia Huebner, Carolin Spatz, Virginie Nägele, Nikolaus Ackermann, Matthias Frosch, Oliver Kurzai, Alexandra Schubert-Unkmeir

  Molecular microbiology. 05/2009;

  Two closely related pathogenic species have evolved in the genus Neisseria: N. meningitidis and N. gonorrhoeae, which occupy different host niches and cause different clinical entities. In contrast to the pathogen N. gonorrhoeae, N. meningitidis is a commensal and only rarely becomes invasive. Littl... [more] Two closely related pathogenic species have evolved in the genus Neisseria: N. meningitidis and N. gonorrhoeae, which occupy different host niches and cause different clinical entities. In contrast to the pathogen N. gonorrhoeae, N. meningitidis is a commensal and only rarely becomes invasive. Little is known about the genetic background of the entirely different lifestyles in these closely related species. Meningococcal NMB1843 encodes a transcriptional regulator of the MarR-family. The gonococcal homologue FarR regulates expression of farAB, mediating fatty acid resistance. We show that NmFarR also directly interacts with NmfarAB. Yet, by contrast to N. gonorrhoeae, no significant sensitivity to fatty acids was observed in a DeltafarR mutant due to intrinsic resistance of meningococci. Further analyses identified an NmFarR repressed protein absent from N. gonorrhoeae. This protein is the meningococcus specific adhesin and vaccine component NadA which has most likely been acquired by horizontal gene transfer. NmFarR binds to a sixteen base pair palindromic repeat within the nadA promoter. De-repression of nadA resulted in significantly higher association of a DeltafarR strain with epithelial cells. Hence NmFarR has gained control over a meningococcus specific gene involved in host colonization and thus contributed to divergent niche adaptation in pathogenic Neisseriae.