Center for Sepsis Control and Care

Jena, Germany

Center for Sepsis Control and Care

Jena, Germany

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Pietrella D.,University of Perugia | Pandey N.,University of Perugia | Gabrielli E.,University of Perugia | Pericolini E.,University of Perugia | And 8 more authors.
European Journal of Immunology | Year: 2013

In a recent report, we demonstrated that distinct members of the secreted aspartic protease (Sap) family of Candida albicans are able to induce secretion of proinflammatory cytokines by human monocytes, independently of their proteolytic activity and specific pH optima. In particular, C. albicans Sap2 and Sap6 potently induced IL-1β, TNF-α, and IL-6 production. Here, we demonstrate that Sap2 and Sap6 proteins trigger IL-1β and IL-18 production through inflammasome activation. This occurs via NLRP3 and caspase-1 activation, which cleaves pro-IL-1β into secreted bioactive IL-1β, a cytokine that was induced by Saps in monocytes, in monocyte-derived macrophages and in dendritic cells. Downregulation of NLRP3 by RNA interference strongly reduced the secretion of bioactive IL-1β. Inflammasome activation required Sap internalization via a clathrin-dependent mechanism, intracellular induction of K+ efflux, and ROS production. Inflammasome activation of monocytes induced by Sap2 and Sap6 differed from that induced by LPS-ATP in several aspects. Our data reveal novel immunoregulatory mechanisms of C. albicans and suggest that Saps contribute to the pathogenesis of candidiasis by fostering rather than evading host immunity. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Bottcher B.,Leibniz Institute for Natural Product Research and Infection Biology | Palige K.,Microfluidic ChipShop GmbH | Jacobsen I.D.,Friedrich - Schiller University of Jena | Jacobsen I.D.,Leibniz Institute for Natural Product Research and Infection Biology | And 4 more authors.
Eukaryotic Cell | Year: 2015

The supply and intracellular homeostasis of trace metals are essential for every living organism. Therefore, the struggle for micronutrients between a pathogen and its host is an important determinant in the infection process. In this work, we focus on the acquisition of zinc by Candida dubliniensis, an emerging pathogen closely related to Candida albicans. We show that the transcription factor Csr1 is essential for C. dubliniensis to regulate zinc uptake mechanisms under zinc limitation: it governs the expression of the zinc transporter genes ZRT1, ZRT2, and ZRT3 and of the zincophore gene PRA1. Exclusively, artificial overexpression of ZRT2 partially rescued the growth defect of a csr1/ mutant in a zinc-restricted environment. Impor-tantly, we found that, in contrast to what is seen in C. albicans, Csr1 (also called Zap1) is not a major regulator of dimorphism in C. dubliniensis. However, although a csr1/strain showed normal germ tube formation, we detected a clear attenuation in virulence using an embryonated chicken egg infection model. We conclude that, unlike in C. albicans, Csr1 seems to be a virulence factor of C. dubliniensis that is not coupled to filamentation but is strongly linked to zinc acquisition during pathogenesis. © 2015, Böttcher et al.


Gow N.A.R.,University of Aberdeen | Hube B.,Leibniz Institute for Natural Product Research and Infection Biology | Hube B.,Friedrich - Schiller University of Jena | Hube B.,Center for Sepsis Control and Care
Current Opinion in Microbiology | Year: 2012

An imbalance of the normal microbial flora, breakage of epithelial barriers or dysfunction of the immune system favour the transition of the human pathogenic yeast Candida albicans from a commensal to a pathogen. C. albicans has evolved to be adapted as a commensal on mucosal surfaces. As a commensal it has also acquired attributes, which are necessary to avoid or overcome the host defence mechanisms. The human host has also co-evolved to recognize and eliminate potential fungal invaders. Many of the fungal genes that have been the focus of this co-evolutionary process encode cell wall components. In this review, we will discuss the transition from commensalism to pathogenesis, the key players of the fungal cell surface that are important for this transition, the role of the morphology and the mechanisms of host recognition and response. © 2012 Elsevier Ltd.


Gabrielli E.,University of Perugia | Pericolini E.,University of Perugia | Luciano E.,University of Perugia | Sabbatini S.,University of Perugia | And 7 more authors.
Infection and Immunity | Year: 2015

We recently demonstrated that the secreted aspartyl proteinases (Saps), Sap2 and Sap6, of Candida albicans have the potential to induce the canonical activation of the NLRP3 inflammasome, leading to the secretion of interleukin-1ß (IL-1ß) and IL-18 via caspase-1 activation. We also observed that the activation of caspase-1 is partially independent from the NLRP3 activation pathway. In this study, we examined whether Sap2 and Sap6 are also able to activate the noncanonical inflammasome pathway in murine macrophages. Our data show that both Sap2 and Sap6 can activate caspase-11 through type I interferon (IFN) production. Caspase-11 cooperates to activate caspase-1, with a subsequent increase of IL-1ß secretion. Endocytosis and internalization of Saps are required for the induction of type I IFN production, which is essential for induction of noncanonical inflammasome activation. Our study indicates a sophisticated interplay between caspase-1 and caspase-11 that connects the canonical and noncanonical pathways of inflammasome activation in response to C. albicans Saps. © 2015, American Society for Microbiology.


Brunke S.,Leibniz Institute for Natural Product Research and Infection Biology | Mogavero S.,Leibniz Institute for Natural Product Research and Infection Biology | Kasper L.,Leibniz Institute for Natural Product Research and Infection Biology | Hube B.,Leibniz Institute for Natural Product Research and Infection Biology | And 2 more authors.
Current Opinion in Microbiology | Year: 2016

Human fungal pathogens are a commonly underestimated cause of severe diseases associated with high morbidity and mortality. Like other pathogens, their survival and growth in the host, as well as subsequent host damage, is thought to be mediated by virulence factors which set them apart from harmless microbes. In this review, we describe and discuss commonly employed strategies for fungal survival and growth in the host and how these affect the host-fungus interactions to lead to disease. While many of these strategies require host-specific virulence factors, more generally any fitness factor which allows growth under host-like conditions can be required for pathogenesis.Furthermore, we briefly summarize how different fungal pathogens are thought to damage the host. We find that in addition to a core of common activities relevant for growth, different groups of fungi employ different strategies which in spite of (or together with) the host's response can lead to disease. © 2016 Elsevier Ltd.


PubMed | Institute for Microbiology and Hygiene, Albert Ludwigs University of Freiburg, Center for Sepsis Control and Care, Friedrich - Alexander - University, Erlangen - Nuremberg and 3 more.
Type: Journal Article | Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2016

Recent population-based cohort studies have questioned the role of pneumococci as the most frequent pathogen causing severe infection in patients after splenectomy. The aim of the study was to define the causative pathogens and clinical presentation of patients with overwhelming postsplenectomy infection (OPSI).In a prospective cohort study in 173 German intensive care units, we searched for patients with and without asplenia and community-acquired severe sepsis/septic shock. Clinical and laboratory variables and survival of patients were assessed.Fifty-two patients with severe sepsis or septic shock with asplenia and 52 without asplenia were included. OPSI patients more often had a history of malignancy (38% vs 17%; P = .016) and had a lower body mass index (24 kg/m(2) vs 28 kg/m(2); P = .004). Streptococcus pneumoniae was detected more frequently in OPSI patients (42% vs 12% without asplenia; P < .001) and more frequently manifested as bloodstream infection (31% vs 6%; P = .002). Gram-negative infection was similar in both groups (12% vs 19%; P = .157). Pneumococcal vaccine coverage of OPSI patients was low overall (42% vs 8% among patients without asplenia; P < .001). Purpura fulminans was a frequent complication, developing in 19% of OPSI patients vs 5% of patients without asplenia (P = .038). The interval between splenectomy and OPSI was 6 years (range, 1 month-50 years). On multivariable Poisson regression, asplenia was the only predictive variable independently associated with pneumococcal sepsis (adjusted relative risk, 2.53 [95% confidence interval, 1.06-6.08]).Pneumococcal infections remain the most important cause of severe sepsis and septic shock following splenectomy.


Bayer O.,Intensive Care Medicine | Schwarzkopf D.,Center for Sepsis Control and Care | Stumme C.,Intensive Care Medicine | Stacke A.,Intensive Care Medicine | And 8 more authors.
Academic Emergency Medicine | Year: 2015

Objectives The objective was to develop and evaluate an early sepsis detection score for the prehospital setting. Methods A retrospective analysis of consecutive patients who were admitted by emergency medical services (EMS) to the emergency department of the Jena University Hospital was performed. Because potential predictors for sepsis should be based on consensus criteria, the following parameters were extracted from the EMS protocol for further analysis: temperature, heart rate (HR), respiratory rate (RR), oxygen saturation (SaO2), Glasgow Coma Scale score, blood glucose, and systolic blood pressure (sBP). Potential predictors were stratified based on inspection of Loess graphs. Backward model selection was performed to select risk factors for the final model. The Prehospital Early Sepsis Detection (PRESEP) score was calculated as the sum of simplified regression weights. Its predictive validity was compared to the Modified Early Warning Score (MEWS), the Robson screening tool, and the BAS 90-30-90. Results A total of 375 patients were included in the derivation sample; 93 (24.8%) of these had sepsis, including 60 patients with severe sepsis and 12 patients with septic shock. Backward model selection identified temperature, HR, RR, SaO2, and sBP for inclusion in the PRESEP score. Simplified weights were as follows: temperature > 38C = 4, temperature < 36C = 1, HR > 90 beats/min = 2, RR > 22 breaths/min = 1, SaO2 < 92% = 2, and sBP < 90 mm Hg = 2. The cutoff value for a possible existing septic disease based on maximum Youden's index was ≥4 (sensitivity 0.85, specificity 0.86, positive predictive value [PPV] 0.66, and negative predictive value [NPV] 0.95). The area under the receiver operating characteristic curve (AUC) of the PRESEP score was 0.93 (95% confidence interval [CI] = 0.89 to 0.96) and was larger than the AUC of the MEWS (0.93 vs. 0.77, p < 0.001). The PRESEP score surpassed MEWS and BAS 90-60-90 for sensitivity (0.74 and 0.62, respectively), specificity (0.75 and 0.83), PPV (0.45 and 0.51), and NPV (0.91 and 0.89). The Robson screening tool had a higher sensitivity and NPV (0.95 and 0.97), but its specificity and PPV were lower (0.43 and 0.32). Conclusions The PRESEP score could be a valuable tool for identifying septic patients in the prehospital setting in the case of suspected infection. It should be prospectively validated. © 2015 by the Society for Academic Emergency Medicine.


PubMed | University of Witwatersrand, Hebrew University of Jerusalem, Service de reanimation medicale, Peking Union Medical College and 6 more.
Type: Journal Article | Journal: Journal of critical care | Year: 2014

Withholding life-sustaining treatments (WHLST) and withdrawing life-sustaining treatments (WDLST) occur in most intensive care units (ICUs) around the world to varying degrees.Speakers from invited faculty of the World Federation of Societies of Intensive and Critical Care Medicine Congress in 2013 with an interest in ethics were approached to participate in an ethics round table. Participants were asked if they agreed with the statement There is no moral difference between withholding and withdrawing a mechanical ventilator. Differences between WHLST and WDLST were discussed. Official statements relating to WHLST and WDLST from intensive care societies, professional bodies, and government statements were sourced, documented, and compared.Sixteen respondents stated that there was no moral difference between withholding or withdrawing a mechanical ventilator, 2 were neutral, and 4 stated that there was a difference. Most ethicists and medical organizations state that there is no moral difference between WHLST and WDLST. A review of guidelines noted that all but 1 of 29 considered WHLST and WDLST as ethically or legally equivalent.Most respondents, practicing intensivists, stated that there is no difference between WHLST and WDLST, supporting most ethicists and professional organizations. A minority of physicians still do not accept their equivalency.


Jaenisch N.,Friedrich - Schiller University of Jena | Popp A.,Friedrich - Schiller University of Jena | Guenther M.,Friedrich - Schiller University of Jena | Schnabel J.,Friedrich - Schiller University of Jena | And 3 more authors.
Neurobiology of Disease | Year: 2014

Following cerebral injuries such as stroke, a structural and functional reorganization of the impaired tissue occurs, which is often accompanied by a re-expression of developmental genes. During brain development, embryonic splice variants of the GABA-synthesizing GAD67 gene (collectively termed EGAD) participate in cell proliferation, migration, and neuronal differentiation. We thus hypothesized an involvement of EGAD in post-ischemic plasticity. EGAD transcripts were up-regulated at early reperfusion times in the injured area following transient middle cerebral artery occlusion (with a peak expression of 4.5-fold at 6. h in C57BL/6 mice). Cell-specific analysis by a combination of radioactive in situ hybridization and immunolabeling revealed EGAD up-regulation in TUNEL-positive neurons. This unexpected cell death-associated expression of EGAD was confirmed in cell culture models of ischemia (combined oxygen-glucose deprivation) and apoptosis (staurosporine). Staurosporine-mediated cell death led to cleaved Caspase-3 activation, a key regulator of apoptosis following stroke. Blocking of staurosporine-associated EGAD expression via antisense RNA treatment reduced cleaved Caspase-3 activation by ~. 30%. In addition to the involvement of EGAD in proliferative processes during brain development, we found here that EGAD participates in cell death under pathophysiological conditions in the adult brain. Re-expression of EGAD in neurons following stroke may play a role in aberrant cell cycle activation, consequently being pro-apoptotic. Our observation of a new GABA related pro-apoptotic mechanism and its successful modification might be of significant clinical relevance. © 2014 Elsevier Inc.


Wagener J.,University of Tübingen | Schneider J.J.,Ludwig Maximilians University of Munich | Baxmann S.,IPF PharmaCeuticals GmbH | Kalbacher H.,University of Tübingen | And 15 more authors.
Journal of Investigative Dermatology | Year: 2013

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has an important role not only in glycolysis but also in nonmetabolic processes, including transcription activation and apoptosis. We report the isolation of a human GAPDH (hGAPDH) (2-32) fragment peptide from human placental tissue exhibiting antimicrobial activity. The peptide was internalized by cells of the pathogenic yeast Candida albicans and initiated a rapid apoptotic mechanism, leading to killing of the fungus. Killing was dose-dependent, with 10 μg ml (3.1 μM) and 100 μg ml hGAPDH (2-32) depolarizing 45% and 90% of the fungal cells in a population, respectively. Experimental C. albicans infection induced epithelial hGAPDH (2-32) expression. Addition of the peptide significantly reduced the tissue damage as compared with untreated experimental infection. Secreted aspartic proteinase (Sap) activity of C. albicans was inhibited by the fragment at higher concentrations, with a median effective dose of 160 mg l -1 (50 μM) for Sap1p and 200 mg l -1 (63 μM) for Sap2p, whereas Sap3 was not inhibited at all. Interestingly, hGAPDH (2-32) induced significant epithelial IL-8 and GM-CSF secretion and stimulated Toll-like receptor 4 expression at low concentrations independently of the presence of C. albicans, without any toxic mucosal effects. In the future, the combination of different antifungal strategies, e.g., a conventional fungicidal with immunomodulatory effects and the inhibition of fungal virulence factors, might be a promising treatment option. © 2013 The Society for Investigative Dermatology.

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