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Jürgen Löffler

About Jürgen Löffler:
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SEEK ID: https://funginet.hki-jena.de/people/14

Location:  Germany

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Julius Maximilians University Würzburg, Department of Internal Medicine II

Country:  Germany

City: 97080 Würzburg

Web page: Not specified

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5th Joint Meeting IMIHM XII & CRC/TR 124
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Programme

Creators: Thomas Wolf, Jürgen Löffler, Annika Tittelbach-Helmrich

Contributor: Thomas Wolf

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Joint Meeting IMIHM XI & CRC/TRANSREGIO 124 Schedule 2017
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Creators: Annika Tittelbach-Helmrich, Jürgen Löffler

Contributor: Thomas Wolf

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Proteome Analysis Reveals the Conidial Surface Protein CcpA Essential for Virulence of the Pathogenic Fungus Aspergillus fumigatus.
FungiNet total, Z2

Abstract (Expand)

Aspergillus fumigatus is a common airborne fungal pathogen of humans and a significant source of mortality in immunocompromised individuals. Here, we provide the most extensive cell wall proteome … profiling to date of A. fumigatus resting conidia, the fungal morphotype pertinent to first contact with the host. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified proteins within the conidial cell wall by hydrogen-fluoride (HF)-pyridine extraction and proteins exposed on the surface using a trypsin-shaving approach. One protein, designated conidial cell wall protein A (CcpA), was identified by both methods and was found to be nearly as abundant as hydrophobic rodlet layer-forming protein RodA. CcpA, an amphiphilic protein, like RodA, peaks in expression during sporulation on resting conidia. Despite high cell wall abundance, the cell surface structure of DeltaccpA resting conidia appeared normal. However, trypsin shaving of DeltaccpA conidia revealed novel surface-exposed proteins not detected on conidia of the wild-type strain. Interestingly, the presence of swollen DeltaccpA conidia led to higher activation of neutrophils and dendritic cells than was seen with wild-type conidia and caused significantly less damage to epithelial cells in vitro In addition, virulence was highly attenuated when cortisone-treated, immunosuppressed mice were infected with DeltaccpA conidia. CcpA-specific memory T cell responses were detectable in healthy human donors naturally exposed to A. fumigatus conidia, suggesting a role for CcpA as a structural protein impacting conidial immunogenicity rather than possessing a protein-intrinsic immunosuppressive effect. Together, these data suggest that CcpA serves as a conidial stealth protein by altering the conidial surface structure to minimize innate immune recognition.IMPORTANCE The mammalian immune system relies on recognition of pathogen surface antigens for targeting and clearance. In the absence of immune evasion strategies, pathogen clearance is rapid. In the case of Aspergillus fumigatus, the successful fungus must avoid phagocytosis in the lung to establish invasive infection. In healthy individuals, fungal spores are cleared by immune cells; however, in immunocompromised patients, clearance mechanisms are impaired. Here, using proteome analyses, we identified CcpA as an important fungal spore protein involved in pathogenesis. A. fumigatus lacking CcpA was more susceptible to immune recognition and prompt eradication and, consequently, exhibited drastically attenuated virulence. In infection studies, CcpA was required for virulence in infected immunocompromised mice, suggesting that it could be used as a possible immunotherapeutic or diagnostic target in the future. In summary, our report adds a protein to the list of those known to be critical to the complex fungal spore surface environment and, more importantly, identifies a protein important for conidial immunogenicity during infection.

Authors: V. Voltersen, M. G. Blango, S. Herrmann, F. Schmidt, Thorsten Heinekamp, M. Strassburger, Thomas Krüger, P. Bacher, Jasmin Lother, Esther Weiß, Kerstin Hünniger, H. Liu, P. Hortschansky, A. Scheffold, Jürgen Löffler, S. Krappmann, S. Nietzsche, Oliver Kurzai, Hermann Einsele, Olaf Kniemeyer, S. G. Filler, U. Reichard, Axel Brakhage

Date Published: No date defined

Journal: MBio

Triple RNA-Seq Reveals Synergy in a Human Virus-Fungus Co-infection Model.
INF, A2, B5

Abstract (Expand)

High-throughput RNA sequencing (RNA-seq) is routinely applied to study diverse biological processes; however, when performed separately on interacting organisms, systemic noise intrinsic to RNA extraction, … library preparation, and sequencing hampers the identification of cross-species interaction nodes. Here, we develop triple RNA-seq to simultaneously detect transcriptomes of monocyte-derived dendritic cells (moDCs) infected with the frequently co-occurring pulmonary pathogens Aspergillus fumigatus and human cytomegalovirus (CMV). Comparing expression patterns after co-infection with those after single infections, our data reveal synergistic effects and mutual interferences between host responses to the two pathogens. For example, CMV attenuates the fungus-mediated activation of pro-inflammatory cytokines through NF-kappaB (nuclear factor kappaB) and NFAT (nuclear factor of activated T cells) cascades, while A. fumigatus impairs viral clearance by counteracting viral nucleic acid-induced activation of type I interferon signaling. Together, the analytical power of triple RNA-seq proposes molecular hubs in the differential moDC response to fungal/viral single infection or co-infection that contribute to our understanding of the etiology and, potentially, clearance of post-transplant infections.

Authors: Bastian Seelbinder, J. Wallstabe, Lothar Marischen, Esther Weiß, S. Wurster, L. Page, C. Loffler, L. Bussemer, A. L. Schmitt, Thomas Wolf, Jörg Linde, L. Cicin-Sain, J. Becker, U. Kalinke, J. Vogel, Gianni Panagiotou, Hermann Einsele, A. J. Westermann, Sascha Schäuble, Jürgen Löffler

Date Published: 17th Nov 2020

Journal: Cell Rep

Reconstituting NK Cells After Allogeneic Stem Cell Transplantation Show Impaired Response to the Fungal Pathogen Aspergillus fumigatus.
INF, A2, A3, C3

Abstract (Expand)

Delayed natural killer (NK) cell reconstitution after allogeneic stem cell transplantation (alloSCT) is associated with a higher risk of developing invasive aspergillosis. The interaction of NK cells … with the human pathogen Aspergillus (A.) fumigatus is mediated by the fungal recognition receptor CD56, which is relocated to the fungal interface after contact. Blocking of CD56 signaling inhibits the fungal mediated chemokine secretion of MIP-1alpha, MIP-1beta, and RANTES and reduces cell activation, indicating a functional role of CD56 in fungal recognition. We collected peripheral blood from recipients of an allograft at defined time points after alloSCT (day 60, 90, 120, 180). NK cells were isolated, directly challenged with live A. fumigatus germ tubes, and cell function was analyzed and compared to healthy age and gender-matched individuals. After alloSCT, NK cells displayed a higher percentage of CD56(bright)CD16(dim) cells throughout the time of blood collection. However, CD56 binding and relocalization to the fungal contact side were decreased. We were able to correlate this deficiency to the administration of corticosteroid therapy that further negatively influenced the secretion of MIP-1alpha, MIP-1beta, and RANTES. As a consequence, the treatment of healthy NK cells ex vivo with corticosteroids abrogated chemokine secretion measured by multiplex immunoassay. Furthermore, we analyzed NK cells regarding their actin cytoskeleton by Structured Illumination Microscopy (SIM) and flow cytometry and demonstrate an actin dysfunction of NK cells shown by reduced F-actin content after fungal co-cultivation early after alloSCT. This dysfunction remains until 180 days post-alloSCT, concluding that further actin-dependent cellular processes may be negatively influenced after alloSCT. To investigate the molecular pathomechansism, we compared CD56 receptor mobility on the plasma membrane of healthy and alloSCT primary NK cells by single-molecule tracking. The results were very robust and reproducible between tested conditions which point to a different molecular mechanism and emphasize the importance of proper CD56 mobility.

Authors: Esther Weiß, J. Schlegel, Ulrich Terpitz, Michael Weber, Jörg Linde, A. L. Schmitt, Kerstin Hünniger, Lothar Marischen, F. Gamon, J. Bauer, C. Loffler, Oliver Kurzai, C. O. Morton, M. Sauer, Hermann Einsele, Jürgen Löffler

Date Published: 5th Oct 2020

Journal: Front Immunol

Candida Species-Dependent Release of IL-12 by Dendritic Cells Induces Different Levels of NK Cell Stimulation.
A2, B4, C3

Abstract (Expand)

BACKGROUND: Candida albicans and Candida glabrata are the 2 most prevalent Candida species causing bloodstream infections. Patterns of innate immune activation triggered by the 2 fungi differ considerably. … METHODS: To analyze human natural killer (NK) cell activation by both species, we performed ex vivo whole-blood infection assays and confrontation assays with primary human NK cells. RESULTS: C. albicans was a stronger activator for isolated human NK cells than C. glabrata. In contrast, activation of blood NK cells, characterized by an upregulated surface exposure of early activation antigen CD69 and death receptor ligand TRAIL, as well as interferon-gamma (IFN-gamma) secretion, was more pronounced during C. glabrata infection. NK cell activation in blood is mediated by humoral mediators released by other immune cells and does not depend on direct activation by fungal cells. Cross-talk between Candida-confronted monocyte-derived dendritic cells (moDC) and NK cells resulted in the same NK activation phenotype as NK cells in human blood. Blocking experiments and cytokine substitution identified interleukin-12 as a critical mediator in regulation of primary NK cells by moDC. CONCLUSIONS: Activation of human NK cells in response to Candida in human blood mainly occurs indirectly by mediators released from monocytic cells.

Authors: A. Marolda, Kerstin Hünniger, S. Bottcher, W. Vivas, Jürgen Löffler, Marc Thilo Figge, Oliver Kurzai

Date Published: 11th Jun 2020

Journal: J Infect Dis

Treatment with etanercept and low monocyte concentration contribute to the risk of invasive aspergillosis in patients post allogeneic stem cell transplantation.
INF, A2, C3

Abstract (Expand)

Invasive aspergillosis (IA) is a life-threatening complication among allogeneic hematopoietic stem cell transplant (alloSCT) recipients. Despite well known risk factors and different available assays, … diagnosis of invasive aspergillosis remains challenging. 103 clinical variables from patients with hematological malignancies and subsequent alloSCT were collected. Associations between collected variables and patients with (n = 36) and without IA (n = 36) were investigated by applying univariate and multivariable logistic regression. The predictive power of the final model was tested in an independent patient cohort (23 IA cases and 25 control patients). Findings were investigated further by in vitro studies, which analysed the effect of etanercept on A. fumigatus-stimulated macrophages at the gene expression and cytokine secretion. Additionally, the release of C-X-C motif chemokine ligand 10 (CXCL10) in patient sera was studied. Low monocyte concentration (p = 4.8 x 10(-06)), severe GvHD of the gut (grade 2-4) (p = 1.08 x 10(-02)) and etanercept treatment of GvHD (p = 3.5 x 10(-03)) were significantly associated with IA. Our studies showed that etanercept lowers CXCL10 concentrations in vitro and ex vivo and down-regulates genes involved in immune responses and TNF-alpha signaling. Our study offers clinicians new information regarding risk factors for IA including low monocyte counts and administration of etanercept. After necessary validation, such information may be used for decision making regarding antifungal prophylaxis or closely monitoring patients at risk.

Authors: T. Zoran, Michael Weber, J. Springer, P. L. White, J. Bauer, A. Schober, C. Loffler, B. Seelbinder, Kerstin Hünniger, Oliver Kurzai, A. Scherag, Sascha Schäuble, C. O. Morton, Hermann Einsele, Jörg Linde, Jürgen Löffler

Date Published: 21st Nov 2019

Journal: Sci Rep

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