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Jan Rybniker
Department I of Internal Medicine, Division of Infectious Diseases, University Hospital Cologne, University of Cologne, Cologne, Germany

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Research paper
Published: 25 August 2021 in EClinicalMedicine
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Background The extent to which children and adolescents contribute to SARS-CoV-2 transmission remains not fully understood. Novel high-capacity testing methods may provide real-time epidemiological data in educational settings helping to establish a rational approach to prevent and minimize SARS-CoV-2 transmission. We investigated whether pooling of samples for SARS-CoV-2 detection by RT-qPCR is a sensitive and feasible high-capacity diagnostic strategy for surveillance of SARS-CoV-2 infections in schools. Methods In this study, students and school staff of 14 educational facilities in Germany were tested sequentially between November 9 and December 23, 2020, two or three times per week for at least three consecutive weeks. Participants were randomized for evaluation of two different age adjusted swab sampling methods (oropharyngeal swabs or buccal swabs compared to saliva swabs using a ‘lolli method'). Swabs were collected and pooled for SARS-CoV-2 RT-qPCR. Individuals of positive pooled tests were retested by RT-qPCR the same or the following day. Positive individuals were quarantined while the SARS-CoV-2 negative individuals remained in class with continued pooled RT-qPCR surveillance. The study is registered with the German Clinical Trials register (registration number: DRKS00023911). Findings 5,537 individuals were eligible and 3970 participants were enroled and included in the analysis. In students, a total of 21,978 swabs were taken and combined in 2218 pooled RT-qPCR tests. We detected 41 positive pooled tests (1·8%) leading to 36 SARS-CoV-2 cases among students which could be identified by individual re-testing. The cumulative 3-week incidence for primary schools was 564/100,000 (6/1064, additionally 1 infection detected in week 4) and 1249/100,000 (29/2322) for secondary schools. In secondary schools, there was no difference in the number of SARS-CoV-2 positive students identified from pooled oropharyngeal swabs compared to those identified from pooled saliva samples (lolli method) (14 vs. 15 cases; 1·3% vs. 1·3%; OR 1.1; 95%-CI 0·5–2·5). A single secondary school accounted for 17 of 36 cases (47%) indicating a high burden of asymptomatic prevalent SARS-CoV-2 cases in the respective school and community. Interpretation In educational settings, SARS-CoV-2 screening by RT-qPCR-based pooled testing with easily obtainable saliva samples is a feasible method to detect incident cases and observe transmission dynamics. Funding Federal Ministry of education and research (BMBF; Project B-FAST in "NaFoUniMedCovid19"; registration number: 01KX2021).

ACS Style

Alexander Joachim; Felix Dewald; Isabelle Suárez; Michael Zemlin; Isabelle Lang; Regine Stutz; Anna Marthaler; Hans Martin Bosse; Nadine Lübke; Juliane Münch; Marie-Annett Bernard; Kathrin Jeltsch; Burkhard Tönshoff; Niklas Weidner; Hans-Georg Kräusslich; Lena Birzele; Johannes Hübner; Patricia Schmied; Melanie Meyer-Bühn; Gibran Horemheb-Rubio; Oliver A. Cornely; Heinz Haverkamp; Gerhard Wiesmüller; Gerd Fätkenheuer; Barbara Hero; Rolf Kaiser; Jörg Dötsch; Jan Rybniker. Pooled RT-qPCR testing for SARS-CoV-2 surveillance in schools - a cluster randomised trial. EClinicalMedicine 2021, 39, 1 .

AMA Style

Alexander Joachim, Felix Dewald, Isabelle Suárez, Michael Zemlin, Isabelle Lang, Regine Stutz, Anna Marthaler, Hans Martin Bosse, Nadine Lübke, Juliane Münch, Marie-Annett Bernard, Kathrin Jeltsch, Burkhard Tönshoff, Niklas Weidner, Hans-Georg Kräusslich, Lena Birzele, Johannes Hübner, Patricia Schmied, Melanie Meyer-Bühn, Gibran Horemheb-Rubio, Oliver A. Cornely, Heinz Haverkamp, Gerhard Wiesmüller, Gerd Fätkenheuer, Barbara Hero, Rolf Kaiser, Jörg Dötsch, Jan Rybniker. Pooled RT-qPCR testing for SARS-CoV-2 surveillance in schools - a cluster randomised trial. EClinicalMedicine. 2021; 39 ():1.

Chicago/Turabian Style

Alexander Joachim; Felix Dewald; Isabelle Suárez; Michael Zemlin; Isabelle Lang; Regine Stutz; Anna Marthaler; Hans Martin Bosse; Nadine Lübke; Juliane Münch; Marie-Annett Bernard; Kathrin Jeltsch; Burkhard Tönshoff; Niklas Weidner; Hans-Georg Kräusslich; Lena Birzele; Johannes Hübner; Patricia Schmied; Melanie Meyer-Bühn; Gibran Horemheb-Rubio; Oliver A. Cornely; Heinz Haverkamp; Gerhard Wiesmüller; Gerd Fätkenheuer; Barbara Hero; Rolf Kaiser; Jörg Dötsch; Jan Rybniker. 2021. "Pooled RT-qPCR testing for SARS-CoV-2 surveillance in schools - a cluster randomised trial." EClinicalMedicine 39, no. : 1.

Journal article
Published: 16 June 2021 in EMBO Molecular Medicine
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Innate immunity triggers responsible for viral control or hyperinflammation in COVID-19 are largely unknown. Here we show that the SARS-CoV-2 spike protein (S-protein) primes inflammasome formation and release of mature interleukin-1β (IL-1β) in macrophages derived from COVID-19 patients but not in macrophages from healthy SARS-CoV-2 naïve individuals. Furthermore, longitudinal analyses reveal robust S-protein-driven inflammasome activation in macrophages isolated from convalescent COVID-19 patients, which correlates with distinct epigenetic and gene expression signatures suggesting innate immune memory after recovery from COVID-19. Importantly, we show that S-protein-driven IL-1β secretion from patient-derived macrophages requires non-specific monocyte pre-activation in vivo to trigger NLRP3-inflammasome signaling. Our findings reveal that SARS-CoV-2 infection causes profound and long-lived reprogramming of macrophages resulting in augmented immunogenicity of the SARS-CoV-2 S-protein, a major vaccine antigen and potent driver of adaptive and innate immune signaling.

ACS Style

Sebastian J Theobald; Alexander Simonis; Theodoros Georgomanolis; Christoph Kreer; Matthias Zehner; Hannah S Eisfeld; Marie‐Christine Albert; Jason Chhen; Susanne Motameny; Florian Erger; Julia Fischer; Jakob J Malin; Jessica Gräb; Sandra Winter; Andromachi Pouikli; Friederike David; Boris Böll; Philipp Koehler; Kanika Vanshylla; Henning Gruell; Isabelle Suárez; Michael Hallek; Gerd Fätkenheuer; Norma Jung; Oliver A Cornely; Clara Lehmann; Peter Tessarz; Janine Altmüller; Peter Nürnberg; Hamid Kashkar; Florian Klein; Manuel Koch; Jan Rybniker. Long‐lived macrophage reprogramming drives spike protein‐mediated inflammasome activation in COVID‐19. EMBO Molecular Medicine 2021, 13, e14150 .

AMA Style

Sebastian J Theobald, Alexander Simonis, Theodoros Georgomanolis, Christoph Kreer, Matthias Zehner, Hannah S Eisfeld, Marie‐Christine Albert, Jason Chhen, Susanne Motameny, Florian Erger, Julia Fischer, Jakob J Malin, Jessica Gräb, Sandra Winter, Andromachi Pouikli, Friederike David, Boris Böll, Philipp Koehler, Kanika Vanshylla, Henning Gruell, Isabelle Suárez, Michael Hallek, Gerd Fätkenheuer, Norma Jung, Oliver A Cornely, Clara Lehmann, Peter Tessarz, Janine Altmüller, Peter Nürnberg, Hamid Kashkar, Florian Klein, Manuel Koch, Jan Rybniker. Long‐lived macrophage reprogramming drives spike protein‐mediated inflammasome activation in COVID‐19. EMBO Molecular Medicine. 2021; 13 (8):e14150.

Chicago/Turabian Style

Sebastian J Theobald; Alexander Simonis; Theodoros Georgomanolis; Christoph Kreer; Matthias Zehner; Hannah S Eisfeld; Marie‐Christine Albert; Jason Chhen; Susanne Motameny; Florian Erger; Julia Fischer; Jakob J Malin; Jessica Gräb; Sandra Winter; Andromachi Pouikli; Friederike David; Boris Böll; Philipp Koehler; Kanika Vanshylla; Henning Gruell; Isabelle Suárez; Michael Hallek; Gerd Fätkenheuer; Norma Jung; Oliver A Cornely; Clara Lehmann; Peter Tessarz; Janine Altmüller; Peter Nürnberg; Hamid Kashkar; Florian Klein; Manuel Koch; Jan Rybniker. 2021. "Long‐lived macrophage reprogramming drives spike protein‐mediated inflammasome activation in COVID‐19." EMBO Molecular Medicine 13, no. 8: e14150.

Journal article
Published: 30 November 2020 in Journal of Antimicrobial Chemotherapy
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ACS Style

Fritz Sörgel; Jakob J Malin; Henning Hagmann; Martina Kinzig; Muhammad Bilal; Dennis A Eichenauer; Oliver Scherf-Clavel; Alexander Simonis; Lobna El Tabei; Uwe Fuhr; Jan Rybniker. Pharmacokinetics of remdesivir in a COVID-19 patient with end-stage renal disease on intermittent haemodialysis. Journal of Antimicrobial Chemotherapy 2020, 76, 825 -827.

AMA Style

Fritz Sörgel, Jakob J Malin, Henning Hagmann, Martina Kinzig, Muhammad Bilal, Dennis A Eichenauer, Oliver Scherf-Clavel, Alexander Simonis, Lobna El Tabei, Uwe Fuhr, Jan Rybniker. Pharmacokinetics of remdesivir in a COVID-19 patient with end-stage renal disease on intermittent haemodialysis. Journal of Antimicrobial Chemotherapy. 2020; 76 (3):825-827.

Chicago/Turabian Style

Fritz Sörgel; Jakob J Malin; Henning Hagmann; Martina Kinzig; Muhammad Bilal; Dennis A Eichenauer; Oliver Scherf-Clavel; Alexander Simonis; Lobna El Tabei; Uwe Fuhr; Jan Rybniker. 2020. "Pharmacokinetics of remdesivir in a COVID-19 patient with end-stage renal disease on intermittent haemodialysis." Journal of Antimicrobial Chemotherapy 76, no. 3: 825-827.

Preprint content
Published: 03 November 2020
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Remdesivir, a drug with provisional approval for the treatment of COVID-19, is not recommended in patients with an estimated glomerular filtration rate ≤ 30 mL/min. Here we provide a first detailed pharmacokinetic assessment of remdesivir and its major metabolites in a patient with end stage renal disease on hemodialysis.

ACS Style

Fritz Soergel; Jakob J. Malin; Henning Hagmann; Martina Kinzig; Muhammad Bilal; Dennis A. Eichenauer; Oliver Scherf-Clavel; Alexander Simonis; Lobna El Tabei; Uwe Fuhr; Jan Rybniker. Pharmacokinetics of remdesivir in a COVID-19 patient with end-stage renal disease on intermittent hemodialysis. 2020, 1 .

AMA Style

Fritz Soergel, Jakob J. Malin, Henning Hagmann, Martina Kinzig, Muhammad Bilal, Dennis A. Eichenauer, Oliver Scherf-Clavel, Alexander Simonis, Lobna El Tabei, Uwe Fuhr, Jan Rybniker. Pharmacokinetics of remdesivir in a COVID-19 patient with end-stage renal disease on intermittent hemodialysis. . 2020; ():1.

Chicago/Turabian Style

Fritz Soergel; Jakob J. Malin; Henning Hagmann; Martina Kinzig; Muhammad Bilal; Dennis A. Eichenauer; Oliver Scherf-Clavel; Alexander Simonis; Lobna El Tabei; Uwe Fuhr; Jan Rybniker. 2020. "Pharmacokinetics of remdesivir in a COVID-19 patient with end-stage renal disease on intermittent hemodialysis." , no. : 1.

Original paper
Published: 02 November 2020 in Infection
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With 1.5 million deaths worldwide in 2018, tuberculosis (TB) remains a major global public health problem. While pulmonary TB (PTB) is the most common manifestation, the proportion of extrapulmonary TB (EPTB) is increasing in low-burden countries. EPTB is a heterogeneous disease entity posing diagnostic and management challenges due to the lack of reliable biomarkers. In this study, we prospectively evaluated clinical data and treatment response which were correlated with different biomarkers. The study was conducted at the University Hospital of Cologne. 20 patients with EPTB were enrolled. We analyzed plasma interferon-γ-inducible protein 10 (IP-10) levels in plasma by ELISA for up to 12 months of treatment. In addition, the QuantiFERON®-TB Gold Plus (QFT® Plus) test was performed during the course of treatment. Clinical data were assessed prospectively and correlated with QFT® Plus and IP-10 levels. Plasma IP-10 levels were found to be significantly increased (p < 0.001) in patients with extensive disease compared to patients with limited disease (cervical lymph node TB) or healthy controls. In patients with clinically confirmed paradoxical reaction (PR), a further increase of IP-10 was noted. IFN-γ measured by the QFT® Plus test did not decrease significantly during the course of treatment. Of note, in four EPTB patients (20%) without radiographic pulmonary involvement, sputum culture was positive for Mycobacterium tuberculosis. Our data demonstrate that IP-10 may be a valuable biomarker for estimation of disease severity in EPTB and monitoring of the disease course in extensive forms. However, IP-10 may be less suitable for diagnosis and monitoring of EPTB patients with limited disease. The QFT® Plus test does not appear to be a suitable marker for therapy monitoring. Sputum should be examined in EPTB patients even in case of normal diagnostic imaging of the chest.

ACS Style

Isabelle Suárez; Samuel Rohr; Melanie Stecher; Clara Lehmann; Sandra Winter; Norma Jung; Vanessa Priesner; Melanie Berger; Christoph Wyen; Max Augustin; Jakob J. Malin; Julia Fischer; Carola Horn; Florian Neuhann; Michael Püsken; Georg Plum; Gerd Fätkenheuer; Jan Rybniker. Plasma interferon-γ-inducible protein 10 (IP-10) levels correlate with disease severity and paradoxical reactions in extrapulmonary tuberculosis. Infection 2020, 49, 437 -445.

AMA Style

Isabelle Suárez, Samuel Rohr, Melanie Stecher, Clara Lehmann, Sandra Winter, Norma Jung, Vanessa Priesner, Melanie Berger, Christoph Wyen, Max Augustin, Jakob J. Malin, Julia Fischer, Carola Horn, Florian Neuhann, Michael Püsken, Georg Plum, Gerd Fätkenheuer, Jan Rybniker. Plasma interferon-γ-inducible protein 10 (IP-10) levels correlate with disease severity and paradoxical reactions in extrapulmonary tuberculosis. Infection. 2020; 49 (3):437-445.

Chicago/Turabian Style

Isabelle Suárez; Samuel Rohr; Melanie Stecher; Clara Lehmann; Sandra Winter; Norma Jung; Vanessa Priesner; Melanie Berger; Christoph Wyen; Max Augustin; Jakob J. Malin; Julia Fischer; Carola Horn; Florian Neuhann; Michael Püsken; Georg Plum; Gerd Fätkenheuer; Jan Rybniker. 2020. "Plasma interferon-γ-inducible protein 10 (IP-10) levels correlate with disease severity and paradoxical reactions in extrapulmonary tuberculosis." Infection 49, no. 3: 437-445.

Journal article
Published: 18 September 2020 in Viruses
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a global health emergency. To improve the understanding of the systemic component of SARS-CoV-2, we investigated if viral load dynamics in plasma and respiratory samples are associated with antibody response and severity of coronavirus disease 2019 (COVID-19). SARS-CoV-2 RNA was found in plasma samples from 14 (44%) out of 32 patients. RNAemia was detected in 5 out of 6 fatal cases. Peak IgG values were significantly lower in mild/moderate than in severe (0.6 (interquartile range, IQR, 0.4–3.2) vs. 11.8 (IQR, 9.9–13.0), adjusted p = 0.003) or critical cases (11.29 (IQR, 8.3–12.0), adjusted p = 0.042). IgG titers were significantly associated with virus Ct (Cycle threshold) value in plasma and respiratory specimens ((ß = 0.4, 95% CI (confidence interval, 0.2; 0.5), p < 0.001 and ß = 0.5, 95% CI (0.2; 0.6), p = 0.002). A classification as severe or a critical case was additionally inversely associated with Ct values in plasma in comparison to mild/moderate cases (ß = −3.3, 95% CI (−5.8; 0.8), p = 0.024 and ß = −4.4, 95% CI (−7.2; 1.6), p = 0.007, respectively). Based on the present data, our hypothesis is that the early stage of SARS-CoV-2 infection is characterized by a primary RNAemia, as a potential manifestation of a systemic infection. Additionally, the viral load in plasma seems to be associated with a worse disease outcome.

ACS Style

Kirsten Alexandra Eberhardt; Charlotte Meyer-Schwickerath; Eva Heger; Elena Knops; Clara Lehmann; Jan Rybniker; Philipp Schommers; Dennis A. Eichenauer; Florian Kurth; Michael Ramharter; Rolf Kaiser; Udo Holtick; Florian Klein; Norma Jung; Veronica Di Cristanziano. RNAemia Corresponds to Disease Severity and Antibody Response in Hospitalized COVID-19 Patients. Viruses 2020, 12, 1045 .

AMA Style

Kirsten Alexandra Eberhardt, Charlotte Meyer-Schwickerath, Eva Heger, Elena Knops, Clara Lehmann, Jan Rybniker, Philipp Schommers, Dennis A. Eichenauer, Florian Kurth, Michael Ramharter, Rolf Kaiser, Udo Holtick, Florian Klein, Norma Jung, Veronica Di Cristanziano. RNAemia Corresponds to Disease Severity and Antibody Response in Hospitalized COVID-19 Patients. Viruses. 2020; 12 (9):1045.

Chicago/Turabian Style

Kirsten Alexandra Eberhardt; Charlotte Meyer-Schwickerath; Eva Heger; Elena Knops; Clara Lehmann; Jan Rybniker; Philipp Schommers; Dennis A. Eichenauer; Florian Kurth; Michael Ramharter; Rolf Kaiser; Udo Holtick; Florian Klein; Norma Jung; Veronica Di Cristanziano. 2020. "RNAemia Corresponds to Disease Severity and Antibody Response in Hospitalized COVID-19 Patients." Viruses 12, no. 9: 1045.

Other
Published: 18 September 2020
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The pandemic spread of the potentially life-threatening disease COVID-19 requires a thorough understanding of the longitudinal dynamics of host responses. Temporal resolution of cellular features associated with a severe disease trajectory will be a pre-requisite for finding disease outcome predictors. Here, we performed a longitudinal multi-omics study using a two-centre German cohort of 13 patients (from Cologne and Kiel, cohort 1). We analysed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. The results from single-cell and bulk transcriptome analyses were validated in two independent cohorts of COVID-19 patients from Bonn (18 patients, cohort 2) and Nijmegen (40 patients, cohort 3), respectively. We observed an increase of proliferating, activated plasmablasts in severe COVID-19, and show a distinct expression pattern related to a hyperactive cellular metabolism of these cells. We further identified a notable expansion of type I IFN-activated circulating megakaryocytes and their progenitors, indicative of emergency megakaryopoiesis, which was confirmed in cohort 2. These changes were accompanied by increased erythropoiesis in the critical phase of the disease with features of hypoxic signalling. Finally, projecting megakaryocyte- and erythroid cell-derived co-expression modules to longitudinal blood transcriptome samples from cohort 3 confirmed an association of early temporal changes of these features with fatal COVID-19 disease outcome. In sum, our longitudinal multi-omics study demonstrates distinct cellular and gene expression dynamics upon SARS-CoV-2 infection, which point to metabolic shifts of circulating immune cells, and reveals changes in megakaryocytes and increased erythropoiesis as important outcome indicators in severe COVID-19 patients.

ACS Style

Joana P. Bernardes; Neha Mishra; Florian Tran; Thomas Bahmer; Lena Best; Johanna I. Blase; Dora Bordoni; Jeanette Franzenburg; Ulf Geisen; Jonathan Josephs-Spaulding; Philipp Koehler; Axel Kuenstner; Elisa Rosati; Anna C. Aschenbrenner; Petra Bacher; Nathan Baran; Teide Boysen; Burkhard Brandt; Niklas Bruse; Jonathan Doerr; Andreas Draeger; Gunnar Elke; David Ellinghaus; Julia Fischer; Michael Forster; Andre Franke; Soeren Franzenburg; Norbert Frey; Anette Friedrichs; Janina Fuss; Andreas Glueck; Jacob Hamm; Finn Hinrichsen; Marc P. Hoeppner; Simon Imm; Ralf Juenker; Sina Kaiser; Ying H. Kan; Rainer Knoll; Christoph Lange; Georg Laue; Clemens Lier; Matthias Lindner; Georgios Marinos; Robert Markewitz; Jacob Nattermann; Rainer Noth; Peter Pickkers; Klaus F. Rabe; Alina Renz; Christoph Roecken; Jan Rupp; Annika Schaffarzyk; Alexander Scheffold; Jonas Schulte-Schrepping; Domagoj Schunck; Dirk Skowasch; Thomas Ulas; Klaus-Peter Wandinger; Michael Wittig; Johannes Zimmermann; Hauke Busch; Bimba F. Hoyer; Christoph Kaleta; Jan Heyckendorf; Matthijs Kox; Jan Rybniker; Stefan Schreiber; Joachim Schultze; Philip Rosenstiel; HCA Lung Biological Network and the Deutsche COVID-19 Omics Initiative (DeCOI). Longitudinal multi-omics analysis identifies responses of megakaryocytes, erythroid cells and plasmablasts as hallmarks of severe COVID-19 trajectories. 2020, 1 .

AMA Style

Joana P. Bernardes, Neha Mishra, Florian Tran, Thomas Bahmer, Lena Best, Johanna I. Blase, Dora Bordoni, Jeanette Franzenburg, Ulf Geisen, Jonathan Josephs-Spaulding, Philipp Koehler, Axel Kuenstner, Elisa Rosati, Anna C. Aschenbrenner, Petra Bacher, Nathan Baran, Teide Boysen, Burkhard Brandt, Niklas Bruse, Jonathan Doerr, Andreas Draeger, Gunnar Elke, David Ellinghaus, Julia Fischer, Michael Forster, Andre Franke, Soeren Franzenburg, Norbert Frey, Anette Friedrichs, Janina Fuss, Andreas Glueck, Jacob Hamm, Finn Hinrichsen, Marc P. Hoeppner, Simon Imm, Ralf Juenker, Sina Kaiser, Ying H. Kan, Rainer Knoll, Christoph Lange, Georg Laue, Clemens Lier, Matthias Lindner, Georgios Marinos, Robert Markewitz, Jacob Nattermann, Rainer Noth, Peter Pickkers, Klaus F. Rabe, Alina Renz, Christoph Roecken, Jan Rupp, Annika Schaffarzyk, Alexander Scheffold, Jonas Schulte-Schrepping, Domagoj Schunck, Dirk Skowasch, Thomas Ulas, Klaus-Peter Wandinger, Michael Wittig, Johannes Zimmermann, Hauke Busch, Bimba F. Hoyer, Christoph Kaleta, Jan Heyckendorf, Matthijs Kox, Jan Rybniker, Stefan Schreiber, Joachim Schultze, Philip Rosenstiel, HCA Lung Biological Network and the Deutsche COVID-19 Omics Initiative (DeCOI). Longitudinal multi-omics analysis identifies responses of megakaryocytes, erythroid cells and plasmablasts as hallmarks of severe COVID-19 trajectories. . 2020; ():1.

Chicago/Turabian Style

Joana P. Bernardes; Neha Mishra; Florian Tran; Thomas Bahmer; Lena Best; Johanna I. Blase; Dora Bordoni; Jeanette Franzenburg; Ulf Geisen; Jonathan Josephs-Spaulding; Philipp Koehler; Axel Kuenstner; Elisa Rosati; Anna C. Aschenbrenner; Petra Bacher; Nathan Baran; Teide Boysen; Burkhard Brandt; Niklas Bruse; Jonathan Doerr; Andreas Draeger; Gunnar Elke; David Ellinghaus; Julia Fischer; Michael Forster; Andre Franke; Soeren Franzenburg; Norbert Frey; Anette Friedrichs; Janina Fuss; Andreas Glueck; Jacob Hamm; Finn Hinrichsen; Marc P. Hoeppner; Simon Imm; Ralf Juenker; Sina Kaiser; Ying H. Kan; Rainer Knoll; Christoph Lange; Georg Laue; Clemens Lier; Matthias Lindner; Georgios Marinos; Robert Markewitz; Jacob Nattermann; Rainer Noth; Peter Pickkers; Klaus F. Rabe; Alina Renz; Christoph Roecken; Jan Rupp; Annika Schaffarzyk; Alexander Scheffold; Jonas Schulte-Schrepping; Domagoj Schunck; Dirk Skowasch; Thomas Ulas; Klaus-Peter Wandinger; Michael Wittig; Johannes Zimmermann; Hauke Busch; Bimba F. Hoyer; Christoph Kaleta; Jan Heyckendorf; Matthijs Kox; Jan Rybniker; Stefan Schreiber; Joachim Schultze; Philip Rosenstiel; HCA Lung Biological Network and the Deutsche COVID-19 Omics Initiative (DeCOI). 2020. "Longitudinal multi-omics analysis identifies responses of megakaryocytes, erythroid cells and plasmablasts as hallmarks of severe COVID-19 trajectories." , no. : 1.

Other
Published: 25 August 2020
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Emerging multidrug-resistant tuberculosis is a major global health challenge. The World Health Organization currently recommends treatment durations of 9–18 months or more for patients with multidrug-resistant tuberculosis. We identified and validated a host-RNA signature to serve as a biomarker for individualized therapy durations for patients with multidrug-resistant tuberculosis. Adult patients with pulmonary tuberculosis were prospectively enrolled into 5 independent cohorts in Germany and Romania. Clinical and microbiological data, and whole-blood for RNA transcriptomic analysis were collected at pre-defined timepoints throughout therapy. Treatment outcomes were ascertained one year after end-of-therapy. A whole-blood RNA therapy end model was developed in a multi-step process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment timepoints. Fifty patients with drug-susceptible tuberculosis and 30 patients with multidrug-resistant tuberculosis were recruited in the German identification cohorts (DS- and MDR-GIC), 28 patients with drug-susceptible tuberculosis and 32 patients with multidrug-resistant tuberculosis in the German validation cohorts (DS- and MDR-GVC), and 52 patients with multidrug-resistant tuberculosis in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model that defined cure-associated end-of-therapy timepoints was derived from the DS- and MDR-GIC data. The model accurately predicted clinical outcomes for patients in the DS-GVC (AUC=0.937 [95%CI:0.899–0.976]) and suggested that cure may be achieved with shorter treatment durations for tuberculosis patients in the MDR-GIC (mean reduction 218.0 days, 34.2%, p One Sentence Summary We identified and validated a transcriptome model based on a 22-gene signature to predict individual treatment durations for patients with multidrug-resistant tuberculosis.

ACS Style

Jan Heyckendorf; Sebastian Marwitz; Maja Reimann; Korkut Avsar; Andrew R Dinardo; Gunar Guenther; Michael Hoelscher; Elmira Ibraim; Barbara Kalsdorf; Stefan H. E. Kaufmann; Irina Kontsevaya; Frank Van Leth; Anna Maria Mandalakas; Florian Maurer; Marius Mueller; Dauerte Nitschkowski; Ioana D. Olaru; Cristina Popa; Andrea Rachow; Thierry Rolling; Jan Rybniker; Helmut J. F. Salzer; Patricia Sanchez-Carballo; Maren Schuhmann; Dagmar Schaub; Victor Spinu; Isabelle Suárez; Elena Terhalle; Markus Unnewehr; January Weiner; Torsten Goldmann; Christoph Lange. A 22-gene transcriptomic model indicating individual therapy durations in multidrug-resistant tuberculosis. 2020, 1 .

AMA Style

Jan Heyckendorf, Sebastian Marwitz, Maja Reimann, Korkut Avsar, Andrew R Dinardo, Gunar Guenther, Michael Hoelscher, Elmira Ibraim, Barbara Kalsdorf, Stefan H. E. Kaufmann, Irina Kontsevaya, Frank Van Leth, Anna Maria Mandalakas, Florian Maurer, Marius Mueller, Dauerte Nitschkowski, Ioana D. Olaru, Cristina Popa, Andrea Rachow, Thierry Rolling, Jan Rybniker, Helmut J. F. Salzer, Patricia Sanchez-Carballo, Maren Schuhmann, Dagmar Schaub, Victor Spinu, Isabelle Suárez, Elena Terhalle, Markus Unnewehr, January Weiner, Torsten Goldmann, Christoph Lange. A 22-gene transcriptomic model indicating individual therapy durations in multidrug-resistant tuberculosis. . 2020; ():1.

Chicago/Turabian Style

Jan Heyckendorf; Sebastian Marwitz; Maja Reimann; Korkut Avsar; Andrew R Dinardo; Gunar Guenther; Michael Hoelscher; Elmira Ibraim; Barbara Kalsdorf; Stefan H. E. Kaufmann; Irina Kontsevaya; Frank Van Leth; Anna Maria Mandalakas; Florian Maurer; Marius Mueller; Dauerte Nitschkowski; Ioana D. Olaru; Cristina Popa; Andrea Rachow; Thierry Rolling; Jan Rybniker; Helmut J. F. Salzer; Patricia Sanchez-Carballo; Maren Schuhmann; Dagmar Schaub; Victor Spinu; Isabelle Suárez; Elena Terhalle; Markus Unnewehr; January Weiner; Torsten Goldmann; Christoph Lange. 2020. "A 22-gene transcriptomic model indicating individual therapy durations in multidrug-resistant tuberculosis." , no. : 1.

Journal article
Published: 12 August 2020 in Scientific Reports
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Host-modulating therapies have become an important focus in the development of novel concepts for improved management of tuberculosis (TB). Previous in vitro studies revealed that the p38 MAP kinase signaling pathway coordinates several inflammatory and stress responses in Mycobacterium tuberculosis (Mtb)-infected host cells. Here we extend these findings and show that in vivo treatment of Mtb-infected C57BL/6 mice with doramapimod, a p38 MAP-kinase inhibitor, results in reduced inflammation, granuloma formation and lung pathology. Moreover, doramapimod, together with standard antibiotic treatment, significantly reduced lung and spleen mycobacterial loads compared to antibiotic treatment alone. Our in vivo data suggest the opportunity to repurpose p38 MAPK inhibitors for adjunct host directed therapies. We also provide first data on safety of p38 MAPK inhibition which is of relevance for future application of these substances in inflammatory diseases and concomitant TB.

ACS Style

Christoph Hölscher; Jessica Gräb; Alexandra Hölscher; Annie Linnea Müller; Stephan C. Schäfer; Jan Rybniker. Chemical p38 MAP kinase inhibition constrains tissue inflammation and improves antibiotic activity in Mycobacterium tuberculosis-infected mice. Scientific Reports 2020, 10, 1 -7.

AMA Style

Christoph Hölscher, Jessica Gräb, Alexandra Hölscher, Annie Linnea Müller, Stephan C. Schäfer, Jan Rybniker. Chemical p38 MAP kinase inhibition constrains tissue inflammation and improves antibiotic activity in Mycobacterium tuberculosis-infected mice. Scientific Reports. 2020; 10 (1):1-7.

Chicago/Turabian Style

Christoph Hölscher; Jessica Gräb; Alexandra Hölscher; Annie Linnea Müller; Stephan C. Schäfer; Jan Rybniker. 2020. "Chemical p38 MAP kinase inhibition constrains tissue inflammation and improves antibiotic activity in Mycobacterium tuberculosis-infected mice." Scientific Reports 10, no. 1: 1-7.

Journal article
Published: 22 July 2020 in Microorganisms
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The prevalence of bacterial pathogens being resistant to antibiotic treatment is increasing worldwide, leading to a severe global health challenge. Simultaneously, the development and approval of new antibiotics stagnated in the past decades, leading to an urgent need for novel approaches to avoid the spread of untreatable bacterial infections in the future. We developed a highly comprehensive screening platform based on quantification of pathogen driven host-cell death to detect new anti-virulence drugs targeting Pseudomonas aeruginosa (Pa) and Salmonella enterica serovar Typhimurium (ST), both known for their emerging antibiotic resistance. By screening over 10,000 small molecules we could identify several substances showing promising effects on Pa and ST pathogenicity in our in vitro infection model. Importantly, we could detect compounds potently inhibiting bacteria induced killing of host cells and one novel comipound with impact on the function of the type 3 secretion system (T3SS) of ST. Thus, we provide proof of concept data of rapid and feasible medium- to high-throughput drug screening assays targeting virulence mechanisms of two major Gram-negative pathogens.

ACS Style

Julia Von Ambüren; Fynn Schreiber; Julia Fischer; Sandra Winter; Edeltraud Van Gumpel; Alexander Simonis; Jan Rybniker. Comprehensive Host Cell-Based Screening Assays for Identification of Anti-Virulence Drugs Targeting Pseudomonas aeruginosa and Salmonella Typhimurium. Microorganisms 2020, 8, 1096 .

AMA Style

Julia Von Ambüren, Fynn Schreiber, Julia Fischer, Sandra Winter, Edeltraud Van Gumpel, Alexander Simonis, Jan Rybniker. Comprehensive Host Cell-Based Screening Assays for Identification of Anti-Virulence Drugs Targeting Pseudomonas aeruginosa and Salmonella Typhimurium. Microorganisms. 2020; 8 (8):1096.

Chicago/Turabian Style

Julia Von Ambüren; Fynn Schreiber; Julia Fischer; Sandra Winter; Edeltraud Van Gumpel; Alexander Simonis; Jan Rybniker. 2020. "Comprehensive Host Cell-Based Screening Assays for Identification of Anti-Virulence Drugs Targeting Pseudomonas aeruginosa and Salmonella Typhimurium." Microorganisms 8, no. 8: 1096.

Other
Published: 22 May 2020
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Evidence has emerged that some healthy individuals with a history of exposure to Mycobacterium tuberculosis (Mtb) can develop protective antibody responses. However, it is not known whether patients with active tuberculosis elicit protective antibodies, and if they do, which bacterial antigens are targeted. To investigate the B cell responses during active infection, we generated a panel of monoclonal antibodies isolated from memory B cells of one patient. The antibodies, members of four distinct B cell clones, were directed against the Mtb phosphate transporter subunit PstS1. Antibodies p4–36 and p4–163 from two different B cell clones showed protective efficacy against Mtb and Mycobacterium bovis-BCG in an ex vivo human whole blood growth inhibition assay. Germline versions of p4–36 and p4–163 could no longer bind Mtb, implying that affinity maturation was vital for their activity. Crystal structures of p4–36 and a closely related clonal variant of p4–163, p4–170, complexed to PstS1 were determined at a resolution of 2.1Å and 2.4Å and revealed that the two antibodies recognize two distinctive epitopes on PstS1. As a proof of principle, p4–36 and p4–163 were used in a passive vaccination setting in aerosol Mtb-infected Balb/c mice, where both antibodies reduced bacterial lung burden by 50% after a single injection prior to Mtb infection. Our study shows that inhibitory B cell responses arise during active tuberculosis and identifies PstS1 as a target for elicitation of anti-Mtb antibodies.

ACS Style

Avia Watson; Hao Li; Bingting Ma; Ronen Weiss; Danielle Bendayan; Lilach Abramovitz; Michael Mor; Erica Pinko; Michal Bar-Oz; Zhenqi Wang; Fengjiao Du; Yu Lu; Jan Rybniker; Hairong Huang; Daniel Barkan; Ye Xiang; Babak Javid; Natalia T Freund. Human Antibodies Targeting a Transporter Mediate Protection Against Tuberculosis. 2020, 1 .

AMA Style

Avia Watson, Hao Li, Bingting Ma, Ronen Weiss, Danielle Bendayan, Lilach Abramovitz, Michael Mor, Erica Pinko, Michal Bar-Oz, Zhenqi Wang, Fengjiao Du, Yu Lu, Jan Rybniker, Hairong Huang, Daniel Barkan, Ye Xiang, Babak Javid, Natalia T Freund. Human Antibodies Targeting a Transporter Mediate Protection Against Tuberculosis. . 2020; ():1.

Chicago/Turabian Style

Avia Watson; Hao Li; Bingting Ma; Ronen Weiss; Danielle Bendayan; Lilach Abramovitz; Michael Mor; Erica Pinko; Michal Bar-Oz; Zhenqi Wang; Fengjiao Du; Yu Lu; Jan Rybniker; Hairong Huang; Daniel Barkan; Ye Xiang; Babak Javid; Natalia T Freund. 2020. "Human Antibodies Targeting a Transporter Mediate Protection Against Tuberculosis." , no. : 1.

Preprint content
Published: 21 May 2020
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Innate immunity triggers responsible for viral control or hyperinflammation in COVID- 19 are largely unknown. Here we show that the SARS-CoV-2 spike protein primes inflammasome activation and interleukin 1-beta (IL-1β) secretion in macrophages derived from COVID-19 patients but not in macrophages from healthy SARS-CoV-2 naïve controls. Chemical NLRP3 inhibition blocks spike protein-induced IL-1β secretion ex vivo. These findings can accelerate research on COVID-19 vaccine design and drug treatment.

ACS Style

Sebastian J. Theobald; Alexander Simonis; Christoph Kreer; Matthias Zehner; Julia Fischer; Marie-Christine Albert; Jakob J. Malin; Jessica Gräb; Sandra Winter; Ute Sandaradura de Silva; Boris Böll; Philipp Köhler; Henning Gruell; Isabelle Suàrez; Michael Hallek; Gerd Fätkenheuer; Norma Jung; Oliver Cornely; Clara Lehmann; Hamid Kashkar; Florian Klein; Jan Rybniker. The SARS-CoV-2 spike protein primes inflammasome-mediated interleukin-1- beta secretion in COVID-19 patient-derived macrophages. 2020, 1 .

AMA Style

Sebastian J. Theobald, Alexander Simonis, Christoph Kreer, Matthias Zehner, Julia Fischer, Marie-Christine Albert, Jakob J. Malin, Jessica Gräb, Sandra Winter, Ute Sandaradura de Silva, Boris Böll, Philipp Köhler, Henning Gruell, Isabelle Suàrez, Michael Hallek, Gerd Fätkenheuer, Norma Jung, Oliver Cornely, Clara Lehmann, Hamid Kashkar, Florian Klein, Jan Rybniker. The SARS-CoV-2 spike protein primes inflammasome-mediated interleukin-1- beta secretion in COVID-19 patient-derived macrophages. . 2020; ():1.

Chicago/Turabian Style

Sebastian J. Theobald; Alexander Simonis; Christoph Kreer; Matthias Zehner; Julia Fischer; Marie-Christine Albert; Jakob J. Malin; Jessica Gräb; Sandra Winter; Ute Sandaradura de Silva; Boris Böll; Philipp Köhler; Henning Gruell; Isabelle Suàrez; Michael Hallek; Gerd Fätkenheuer; Norma Jung; Oliver Cornely; Clara Lehmann; Hamid Kashkar; Florian Klein; Jan Rybniker. 2020. "The SARS-CoV-2 spike protein primes inflammasome-mediated interleukin-1- beta secretion in COVID-19 patient-derived macrophages." , no. : 1.

Original article
Published: 27 April 2020 in Mycoses
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Objectives Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates Coronavirus disease 19 (COVID‐19) associated invasive aspergillosis at a single center in Cologne, Germany. Methods A retrospective chart review of all patients with COVID‐19 ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Germany. Results COVID‐19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS. Conclusion Clinicians caring for patients with ARDS due to COVID‐19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co‐infection.

ACS Style

Philipp Koehler; Oliver A. Cornely; Bernd W. Böttiger; Fabian Dusse; Dennis A. Eichenauer; Frieder Fuchs; Michael Hallek; Norma Jung; Florian Klein; Thorsten Persigehl; Jan Rybniker; Matthias Kochanek; Boris Böll; Alexander Shimabukuro‐Vornhagen. COVID‐19 associated pulmonary aspergillosis. Mycoses 2020, 63, 528 -534.

AMA Style

Philipp Koehler, Oliver A. Cornely, Bernd W. Böttiger, Fabian Dusse, Dennis A. Eichenauer, Frieder Fuchs, Michael Hallek, Norma Jung, Florian Klein, Thorsten Persigehl, Jan Rybniker, Matthias Kochanek, Boris Böll, Alexander Shimabukuro‐Vornhagen. COVID‐19 associated pulmonary aspergillosis. Mycoses. 2020; 63 (6):528-534.

Chicago/Turabian Style

Philipp Koehler; Oliver A. Cornely; Bernd W. Böttiger; Fabian Dusse; Dennis A. Eichenauer; Frieder Fuchs; Michael Hallek; Norma Jung; Florian Klein; Thorsten Persigehl; Jan Rybniker; Matthias Kochanek; Boris Böll; Alexander Shimabukuro‐Vornhagen. 2020. "COVID‐19 associated pulmonary aspergillosis." Mycoses 63, no. 6: 528-534.

Review
Published: 13 April 2020 in Applied Sciences
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Despite global efforts to contain tuberculosis (TB), the disease remains a leading cause of morbidity and mortality worldwide, further exacerbated by the increased resistance to antibiotics displayed by the tubercle bacillus Mycobacterium tuberculosis. In order to treat drug-resistant TB, alternative or complementary approaches to standard anti-TB regimens are being explored. An area of active research is represented by host-directed therapies which aim to modulate the host immune response by mitigating inflammation and by promoting the antimicrobial activity of immune cells. Additionally, compounds that reduce the virulence of M. tuberculosis, for instance by targeting the major virulence factor ESX-1, are being given increased attention by the TB research community. This review article summarizes the current state of the art in the development of these emerging therapies against TB.

ACS Style

Raphael Gries; Claudia Sala; Jan Rybniker. Host-Directed Therapies and Anti-Virulence Compounds to Address Anti-Microbial Resistant Tuberculosis Infection. Applied Sciences 2020, 10, 2688 .

AMA Style

Raphael Gries, Claudia Sala, Jan Rybniker. Host-Directed Therapies and Anti-Virulence Compounds to Address Anti-Microbial Resistant Tuberculosis Infection. Applied Sciences. 2020; 10 (8):2688.

Chicago/Turabian Style

Raphael Gries; Claudia Sala; Jan Rybniker. 2020. "Host-Directed Therapies and Anti-Virulence Compounds to Address Anti-Microbial Resistant Tuberculosis Infection." Applied Sciences 10, no. 8: 2688.

Case reports
Published: 03 January 2020 in Infection
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Central nervous system (CNS) tuberculomas are a challenging manifestation of extrapulmonary tuberculosis often leading to neurological complications and post-treatment sequelae. The role of adjunctive corticosteroid treatment is not fully understood. Most guidelines on management of tuberculosis do not distinguish between tuberculous meningitis and CNS tuberculomas in terms of corticosteroid therapy. We describe five patients with CNS tuberculomas who required intensified dexamethasone treatment for several months, in two cases up to 18 months. These patients were initially treated with the standard four-drug tuberculosis regimen and adjuvant dexamethasone. Neurological symptoms improved rapidly. However, multiple attempts to reduce or discontinue corticosteroids according to guideline recommendations led to clinical deterioration with generalized seizures or new CNS lesions. Thus, duration of adjunctive corticosteroid therapy was extended eventually leading to clinical cure and resolution of lesions. In contrast to tuberculous meningitis, the treatment for CNS tuberculomas appears to require a prolonged administration of corticosteroids. These findings need to be verified in controlled clinical studies.

ACS Style

Isabelle Suárez; Henning Grüll; Jan Heyckendorf; Sarah Fünger; Thorsten Lichtenstein; Norma Jung; Clara Lehmann; Markus Unnewehr; Gerd Fätkenheuer; Christoph Lange; Jan Rybniker. Intensified adjunctive corticosteroid therapy for CNS tuberculomas. Infection 2020, 48, 289 -293.

AMA Style

Isabelle Suárez, Henning Grüll, Jan Heyckendorf, Sarah Fünger, Thorsten Lichtenstein, Norma Jung, Clara Lehmann, Markus Unnewehr, Gerd Fätkenheuer, Christoph Lange, Jan Rybniker. Intensified adjunctive corticosteroid therapy for CNS tuberculomas. Infection. 2020; 48 (2):289-293.

Chicago/Turabian Style

Isabelle Suárez; Henning Grüll; Jan Heyckendorf; Sarah Fünger; Thorsten Lichtenstein; Norma Jung; Clara Lehmann; Markus Unnewehr; Gerd Fätkenheuer; Christoph Lange; Jan Rybniker. 2020. "Intensified adjunctive corticosteroid therapy for CNS tuberculomas." Infection 48, no. 2: 289-293.

Journal article
Published: 01 November 2019 in Antimicrobial Agents and Chemotherapy
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Mycobacterium abscessus, a rapidly growing non-tuberculous mycobacterium (NTM), is increasingly recognized as an important pathogen causing soft tissue and lung infections as well as severe disseminated infections in immunocompromised patients (1, 2).…

ACS Style

Jakob J. Malin; Sandra Winter; Edeltraud van Gumpel; Georg Plum; Jan Rybniker. Extremely Low Hit Rate in a Diverse Chemical Drug Screen Targeting Mycobacterium abscessus. Antimicrobial Agents and Chemotherapy 2019, 63, 1 .

AMA Style

Jakob J. Malin, Sandra Winter, Edeltraud van Gumpel, Georg Plum, Jan Rybniker. Extremely Low Hit Rate in a Diverse Chemical Drug Screen Targeting Mycobacterium abscessus. Antimicrobial Agents and Chemotherapy. 2019; 63 (11):1.

Chicago/Turabian Style

Jakob J. Malin; Sandra Winter; Edeltraud van Gumpel; Georg Plum; Jan Rybniker. 2019. "Extremely Low Hit Rate in a Diverse Chemical Drug Screen Targeting Mycobacterium abscessus." Antimicrobial Agents and Chemotherapy 63, no. 11: 1.

Journal article
Published: 25 October 2019 in Deutsches Aerzteblatt Online
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ACS Style

Isabelle Suárez; Sarah Maria Fünger; Stefan Kröger; Jessica Rademacher; Gerd Fätkenheuer; Jan Rybniker. The Diagnosis and Treatment of Tuberculosis. Deutsches Aerzteblatt Online 2019, 1 .

AMA Style

Isabelle Suárez, Sarah Maria Fünger, Stefan Kröger, Jessica Rademacher, Gerd Fätkenheuer, Jan Rybniker. The Diagnosis and Treatment of Tuberculosis. Deutsches Aerzteblatt Online. 2019; ():1.

Chicago/Turabian Style

Isabelle Suárez; Sarah Maria Fünger; Stefan Kröger; Jessica Rademacher; Gerd Fätkenheuer; Jan Rybniker. 2019. "The Diagnosis and Treatment of Tuberculosis." Deutsches Aerzteblatt Online , no. : 1.

Review
Published: 01 October 2019 in The Lancet Infectious Diseases
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In high-income countries, the presentation of tuberculosis is changing, primarily because of migration, and understanding the specific health needs of susceptible populations is becoming increasingly important. Although disseminated tuberculosis is well documented in HIV-positive patients, the disease is poorly described and less expected in HIV-negative individuals. In this Grand Round, we report eight HIV-negative refugees, who presented with extensively disseminated tuberculosis. We discuss the multifactorial causes, such as deprivations during long journeys, precarious living conditions, and the experience of violence, which might add to nutritional factors and chronic disorders, eventually resulting in a state of predisposition to immune deficiency. We also show that disseminated tuberculosis is often difficult to diagnose when pulmonary symptoms are absent. Communication difficulties between refugees and health-care workers are another major hurdle, and every effort should be made to get a valid patient history. This medical history is crucial to guide imaging and other diagnostic procedures to establish a definite diagnosis, which should be confirmed by a positive tuberculosis culture. Because many of these patients are at risk for multidrug-resistant tuberculosis, drug susceptibility testing is imperative to guide therapy. In the absence of treatment guidelines for this entity, clinicians can determine treatment duration according to recommendations provided for extrapulmonary tuberculosis and affected organs. Paradoxical expansion of tuberculous lesions during therapy should be treated with corticosteroids. In many cases, treatment duration must be individualised and might even exceed 12 months.

ACS Style

Isabelle Suárez; Sarah Maria Fünger; Norma Jung; Clara Lehmann; Robert Peter Reimer; Dennis Mehrkens; Anne Bunte; Georg Plum; Natalie Jaspers; Matthias Schmidt; Gerd Fätkenheuer; Jan Rybniker. Severe disseminated tuberculosis in HIV-negative refugees. The Lancet Infectious Diseases 2019, 19, e352 -e359.

AMA Style

Isabelle Suárez, Sarah Maria Fünger, Norma Jung, Clara Lehmann, Robert Peter Reimer, Dennis Mehrkens, Anne Bunte, Georg Plum, Natalie Jaspers, Matthias Schmidt, Gerd Fätkenheuer, Jan Rybniker. Severe disseminated tuberculosis in HIV-negative refugees. The Lancet Infectious Diseases. 2019; 19 (10):e352-e359.

Chicago/Turabian Style

Isabelle Suárez; Sarah Maria Fünger; Norma Jung; Clara Lehmann; Robert Peter Reimer; Dennis Mehrkens; Anne Bunte; Georg Plum; Natalie Jaspers; Matthias Schmidt; Gerd Fätkenheuer; Jan Rybniker. 2019. "Severe disseminated tuberculosis in HIV-negative refugees." The Lancet Infectious Diseases 19, no. 10: e352-e359.

Full paper
Published: 23 April 2019 in Chemistry - A European Journal
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Cyclomarins are highly potent antimycobacterial and antiplasmodial cyclopeptides isolated from a marine bacterium (Streptomyces sp.). Previous studies have identified the target proteins and elucidated a novel mode of action, however there are currently only a few studies examining the structure‐activity relationship (SAR) for both pathogens. Herein, we report the synthesis and biological evaluation of 17 novel desoxycyclomarin‐inspired analogues. Optimiza¬tion via side chain modifications of the non‐canonical amino acids led to potent lead structures for each pathogen.

ACS Style

Alexander Kiefer; Chantal D. Bader; Jana Held; Anna Esser; Jan Rybniker; Martin Empting; Rolf Müller; Uli Kazmaier. Synthesis of New Cyclomarin Derivatives and Their Biological Evaluation towards Mycobacterium Tuberculosis and Plasmodium Falciparum. Chemistry - A European Journal 2019, 25, 8894 -8902.

AMA Style

Alexander Kiefer, Chantal D. Bader, Jana Held, Anna Esser, Jan Rybniker, Martin Empting, Rolf Müller, Uli Kazmaier. Synthesis of New Cyclomarin Derivatives and Their Biological Evaluation towards Mycobacterium Tuberculosis and Plasmodium Falciparum. Chemistry - A European Journal. 2019; 25 (37):8894-8902.

Chicago/Turabian Style

Alexander Kiefer; Chantal D. Bader; Jana Held; Anna Esser; Jan Rybniker; Martin Empting; Rolf Müller; Uli Kazmaier. 2019. "Synthesis of New Cyclomarin Derivatives and Their Biological Evaluation towards Mycobacterium Tuberculosis and Plasmodium Falciparum." Chemistry - A European Journal 25, no. 37: 8894-8902.

Journal article
Published: 08 February 2019 in Nature Communications
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Corticosteroids are host-directed drugs with proven beneficial effect on survival of tuberculosis (TB) patients, but their precise mechanisms of action in this disease remain largely unknown. Here we show that corticosteroids such as dexamethasone inhibit necrotic cell death of cells infected with Mycobacterium tuberculosis (Mtb) by facilitating mitogen-activated protein kinase phosphatase 1 (MKP-1)-dependent dephosphorylation of p38 MAPK. Characterization of infected mixed lineage kinase domain-like (MLKL) and tumor necrosis factor receptor 1 (TNFR1) knockout cells show that the underlying mechanism is independent from TNFα-signaling and necroptosis. Our results link corticosteroid function and p38 MAPK inhibition to abrogation of necrotic cell death mediated by mitochondrial membrane permeability transition, and open new avenues for research on novel host-directed therapies (HDT). Corticosteroids are host-directed drugs that enhance survival of tuberculosis patients through unclear mechanisms. Here, Gräb et al. show that corticosteroids inhibit necrotic death of cells infected with Mycobacterium tuberculosis by facilitating MKP-1-dependent dephosphorylation of p38 MAPK.

ACS Style

Jessica Gräb; Isabelle Suárez; Edeltraud Van Gumpel; Sandra Winter; Fynn Schreiber; Anna Esser; Christoph Hölscher; Melanie Fritsch; Marc Herb; Michael Schramm; Laurens Wachsmuth; Christian P. Pallasch; Manolis Pasparakis; Hamid Kashkar; Jan Rybniker. Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition. Nature Communications 2019, 10, 1 -14.

AMA Style

Jessica Gräb, Isabelle Suárez, Edeltraud Van Gumpel, Sandra Winter, Fynn Schreiber, Anna Esser, Christoph Hölscher, Melanie Fritsch, Marc Herb, Michael Schramm, Laurens Wachsmuth, Christian P. Pallasch, Manolis Pasparakis, Hamid Kashkar, Jan Rybniker. Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition. Nature Communications. 2019; 10 (1):1-14.

Chicago/Turabian Style

Jessica Gräb; Isabelle Suárez; Edeltraud Van Gumpel; Sandra Winter; Fynn Schreiber; Anna Esser; Christoph Hölscher; Melanie Fritsch; Marc Herb; Michael Schramm; Laurens Wachsmuth; Christian P. Pallasch; Manolis Pasparakis; Hamid Kashkar; Jan Rybniker. 2019. "Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition." Nature Communications 10, no. 1: 1-14.