Publications

  1. Research Outputs (Up to 2022) A comprehensive listing of research outputs.

1.1. 2022 Target capture sequencing reveals a monoclonal outbreak of respiratory syncytial virus B infections among adult hematologic patients Background Respiratory syncytial virus (RSV) causes community-acquired respiratory tract infections during winter. However, outbreaks in hospitals also occur repeatedly. In particular, patients with hematologic malignancies are at an increased risk for a severe and potentially fatal course of RSV infection. Here we present the investigation of an RSV outbreak in a hematology ward for adults following the ORION statement.

Methods An epidemiologic and molecular outbreak analysis was performed. We developed and employed a minimal oligonucleotide probe set in target capture probe sequencing that allows cost-effective RSV-A or -B capturing to reconstruct RSV genomes from clinical samples.

Results Four adult patients were involved in the outbreak caused by RSV-B in March 2019. The enforcement of the pre-existing infection control measures by effective training of hospital staff contributed to a successful containment. PCR-based RSV screening on the ward enabled early detection of new cases and rapid isolation measures. The molecular analysis demonstrated that the outbreak sequences were highly related and distinct to other RSV-B strains circulating at the same time.

Conclusions A multimodal infection control concept is essential for the timely detection and control of RSV outbreaks in patients with hematological disease. Among other measures, preventive screening for respiratory viruses is recommended. Furthermore, the integration of conventional and molecular epidemiology, such as whole-genome sequencing and variant calling, significantly contributes to the understanding of transmission pathways. Based on this, appropriate conclusions can be drawn for targeted prevention measures that have prepared us for the COVID-19 pandemic beyond the RSV approach described here. General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School (MHH), Carl‑Neuberg‑Straße 1, 30625 Hannover, Germany, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistraße 52, 20251 Hamburg, Germany., Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), Carl‑Neuberg‑Straße 1, 30625 Hannover, Germany, Institute of Virology, Hannover Medical School (MHH), Carl‑Neuberg‑Str. 1, 30625 Hannover, Germany, Institute for Experimental Virology; Twincore‑Centre for Experimental and Clinical Infection Research; a joint venture of Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), Feodor‑Lynen‑Straße 7, 30625 Hannover, Germany, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany. Contributors: Baier, C., Huang, J., Reumann, K., Indenbirken, D., Thol, F., Koenecke, C., Ebadi, E., Heim, A., Bange, F., Haid, S., Pietschmann, T., Fischer, N. Pages: 88 Publication date: 21.06.2022 REQUIRED: Peer-reviewed: Yes Publication information Journal: ANTIMICROB RESIST IN Volume: 11 Issue number: 1 Article number: 88 ISSN (Print): 2047-2994 Ratings: Scopus rating (2022): CiteScore 10.2 UKE base score (2022): Rating 16.727 Original language: English DOIs: 10.1186/s13756-022-01120-z Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

Population dynamics in colonizing vancomycin-resistant Enterococcus faecium isolated from immunosuppressed patients OBJECTIVES: Vancomycin-resistant Enterococcus faecium and Enterococcus faecalis (VRE) are a common cause of healthcare-associated infections. Whole genome sequencing-based typing methods yield the highest discriminatory power for outbreak surveillance in the hospital. We analysed the clonal composition of enteric VRE populations of at-risk patients over several weeks to characterise VRE population diversity and dynamics.

METHODS: Five bone marrow transplant recipients (three colonised with vanA-positive isolates, two colonised with vanB-positive isolates) contributed three rectal swabs over a course of several weeks. Fourteen VRE colonies per swab were analysed by core genome multi locus sequence typing (cgMLST) and typing of the van-element.

RESULTS: VRE populations were clonally diverse in three of five patients, and population composition changed dynamically over the time of observation. Besides new acquisition of VRE isolates, shared van-elements localised on nearly identical plasmids between clonally different isolates indicate horizontal gene transfer as a mechanism behind VRE population diversity within single patients.

CONCLUSION: Outbreak detection relies on typing of isolates, usually by analysing one isolate per patient. We here show that this approach is insufficient for outbreak surveillance of VRE in highly vulnerable patients, as it does not take into account VRE population heterogeneity and horizontal gene transfer of the resistance element.

General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Department of Stem Cell Transplantation Contributors: Both, A., Kruse, F., Mirwald, N., Franke, G., Christner, M., Huang, J., Hansen, J. L., Kröger, N., Berneking, L., Lellek, H., Aepfelbacher, M., Rohde, H. REQUIRED books only: Number of pages: 7 Pages: 267-273 Publication date: 03.2022 REQUIRED: Peer-reviewed: Yes Early online date: 05.02.2022 Publication information Journal: J GLOB ANTIMICROB RE Volume: 28 ISSN (Print): 2213-7165 Ratings: Scopus rating (2022): CiteScore 7 UKE base score (2022): Rating 11.074 Original language: English DOIs: 10.1016/j.jgar.2022.01.027 Comment Deanary Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

Source: PubMed Source ID: 35134550 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

A pharmacokinetic-pharmacodynamic (PKPD) model-based analysis of tedizolid against enterococci using the hollow-fibre infection model Background Tedizolid is a novel oxazolidinone antibiotic. Considering the higher antibacterial effect in immunocompetent compared with immunosuppressed animals, it is not recommended in immunocompromised patients.

Objectives In this study, we assessed the ‘pure’ pharmacokinetic-pharmacodynamic (PKPD) relationship for tedizolid against Enterococcus in the hollow-fibre infection model (HFIM).

Methods Unbound plasma concentration time profiles (200–5000 mg/day IV) were simulated in the HFIM over 120 h against an Enterococcus faecalis strain and two clinical isolates of Enterococcus faecium (VRE-vanB and VRE-vanA). Next, a PKPD model describing tedizolid efficacy against bacterial isolates was developed. A population PK model was linked to the developed PKPD model and utilized to predict the bacterial kinetics in plasma and in target tissues [adipose, muscle, epithelial lining fluid (ELF) and sputum] over 120 h of therapy.

Results The PKPD model adequately described the bacterial kill kinetics for all bacterial populations. At the human recommended dose of 200 mg/day, bacterial growth was predicted in plasma and all tissues, except for ELF. Bacteriostasis was observed only at a higher dose of 1200 mg/day over 120 h. An fAUC/MIC of 80 related to stasis over 120 h. Subpopulations resistant to 3 × MIC were amplified in plasma and target tissues, except for ELF, at doses of 200–800 mg/day.

Conclusions The human dose of 200 mg/day was insufficient to suppress bacterial growth in the HFIM, indicating that further components contribute to the clinical effect of tedizolid. This study supports the warning/precaution for tedizolid to limit its use in immunocompromised patients. General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany, Department of Clinical Pharmacology, General Hospital (AKH), Medical University of Vienna, Vienna, Austria Contributors: Iqbal, K., Rohde, H., Huang, J., Tikiso, T., Amann, L., Zeitlinger, M., Wicha, S. REQUIRED books only: Number of pages: 9 Pages: 2470–2478 Publication date: 25.08.2022 REQUIRED: Peer-reviewed: Yes Publication information Journal: J ANTIMICROB CHEMOTH Volume: 77 Issue number: 9 ISSN (Print): 0305-7453 Ratings: Scopus rating (2022): CiteScore 8.9 UKE base score (2022): Rating 14.532 Original language: English DOIs: 10.1093/jac/dkac183 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

Mechanisms of CD8+ T cell failure in chronic hepatitis E virus infection Background & Aims In immunosuppressed patients, persistent HEV infection is common and may lead to cirrhosis and liver failure. HEV clearance depends on an effective virus-specific CD8+ T-cell response; however, the knowledge gap around HEV-specific CD8+ T-cell epitopes has hindered analysis of the mechanisms of T-cell failure in persistent infection.

Methods We comprehensively studied HEV-specific CD8+ T-cell responses in 46 patients with self-limiting (n = 34) or chronic HEV infection (n = 12), by epitope-specific expansion, functional testing, ex vivo peptide HLA class I tetramer multi-parametric staining, and viral sequence analysis.

Results We identified 25 HEV-specific CD8+ T-cell epitopes restricted by 9 different HLA class I alleles. In self-limiting HEV infection, HEV-specific CD8+ T cells were vigorous, contracted after resolution of infection, and formed functional memory responses. In contrast, in chronic infection, the HEV-specific CD8+ T-cell response was diminished, declined over time, and displayed phenotypic features of exhaustion. However, improved proliferation of HEV-specific CD8+ T cells, increased interferon-γ production and evolution of a memory-like phenotype were observed upon reduction of immunosuppression and/or ribavirin treatment and were associated with viral clearance. In 1 patient, mutational viral escape in a targeted CD8+ T-cell epitope contributed to CD8+ T-cell failure.

Conclusion Chronic HEV infection is associated with HEV-specific CD8+ T-cell exhaustion, indicating that T-cell exhaustion driven by persisting antigen recognition also occurs in severely immunosuppressed hosts. Functional reinvigoration of virus-specific T cells is at least partially possible when antigen is cleared. In a minority of patients, viral escape also contributes to HEV-specific CD8+ T-cell failure and thus needs to be considered in personalized immunotherapeutic approaches.

Lay summary Hepatitis E virus (HEV) infection is usually cleared spontaneously (without treatment) in patients with fully functioning immune systems. In immunosuppressed patients, chronic HEV infection is common and can progress rapidly to cirrhosis and liver failure. Herein, we identified the presence of HEV-specific CD8+ T cells (a specific type of immune cell that can target HEV) in immunosuppressed patients, but we show that these cells do not function properly. This dysfunction appears to play a role in the development of chronic HEV infection in vulnerable patients. General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Department of Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Diseases, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 70085 Freiburg, Germany., Institute of Virology, University Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany. Contributors: Kemming, J., Gundlach, S., Panning, M., Huzly, D., Huang, J., Lütgehetmann, M., Fischer, N., Neumann-Haefelin, C. REQUIRED books only: Number of pages: 13 Pages: 978-990 Publication date: 16.05.2022 REQUIRED: Peer-reviewed: Yes Publication information Journal: J HEPATOL Volume: 77 Issue number: 4 ISSN (Print): 0168-8278 Ratings: Scopus rating (2022): CiteScore 40.4 UKE base score (2022): Rating 75.642 Original language: English DOIs: https://doi.org/10.1016/j.jhep.2022.05.019 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

Respiratory Syncytial Virus Two-Step Infection Screen Reveals Inhibitors of Early and Late Life Cycle Stages Human respiratory syncytial virus (hRSV) infection is a leading cause of severe respiratory tract infections. Effective, directly acting antivirals against hRSV are not available. We aimed to discover new and chemically diverse candidates to enrich the hRSV drug development pipeline. We used a two-step screen that interrogates compound efficacy after primary infection and a consecutive virus passaging. We resynthesized selected hit molecules and profiled their activities with hRSV lentiviral pseudotype cell entry, replicon, and time-of-addition assays. The breadth of antiviral activity was tested against recent RSV clinical strains and human coronavirus (hCoV-229E), and in pseudotype-based entry assays with non-RSV viruses. Screening 6,048 molecules, we identified 23 primary candidates, of which 13 preferentially scored in the first and 10 in the second rounds of infection, respectively. Two of these molecules inhibited hRSV cell entry and selected for F protein resistance within the fusion peptide. One molecule inhibited transcription/replication in hRSV replicon assays, did not select for phenotypic hRSV resistance and was active against non-hRSV viruses, including hCoV-229E. One compound, identified in the second round of infection, did not measurably inhibit hRSV cell entry or replication/transcription. It selected for two coding mutations in the G protein and was highly active in differentiated BCi-NS1.1 lung cells. In conclusion, we identified four new hRSV inhibitor candidates with different modes of action. Our findings build an interesting platform for medicinal chemistry-guided derivatization approaches followed by deeper phenotypical characterization in vitro and in vivo with the aim of developing highly potent hRSV drugs.

General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Research Department for Viral Zoonoses-One Health, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany; Institute for Virology, University for Veterinary Medicine, Hannover, Germany., Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Université Paris-Saclay, CNRS UMR3348, Université Paris Sud, Orsay, France. Contributors: Sake, S. M., Kosch, C., Blockus, S., Haid, S., Gunesch, A. P., Zhang, X., Friesland, M., Trummer, S. B., Grethe, C., Kühnel, A., Rückert, J., Duprex, W. P., Huang, J., Rameix-Welti, M., Empting, M., Fischer, N., Hirsch, A. K. H., Schulz, T. F., Pietschmann, T. Publication date: 20.12.2022 REQUIRED: Peer-reviewed: Yes Early online date: 08.11.2022 Publication information Journal: ANTIMICROB AGENTS CH Volume: 66 Issue number: 12 Article number: e0103222 ISSN (Print): 0066-4804 Ratings: Scopus rating (2022): CiteScore 9.8 UKE base score (2022): Rating 15.653 Original language: English DOIs: 10.1128/aac.01032-22 Source: PubMed Source ID: 36346232 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

1.2. 2021 Yersinia remodels epigenetic histone modifications in human macrophages Various pathogens systematically reprogram gene expression in macrophages, but the underlying mechanisms are largely unknown. We investigated whether the enteropathogen Yersinia enterocolitica alters chromatin states to reprogram gene expression in primary human macrophages. Genome-wide chromatin immunoprecipitation (ChIP) seq analyses showed that pathogen-associated molecular patterns (PAMPs) induced up- or down-regulation of histone modifications (HMod) at approximately 14500 loci in promoters and enhancers. Effectors of Y. enterocolitica reorganized about half of these dynamic HMod, with the effector YopP being responsible for about half of these modulatory activities. The reorganized HMod were associated with genes involved in immune response and metabolism. Remarkably, the altered HMod also associated with 61% of all 534 known Rho GTPase pathway genes, revealing a new level in Rho GTPase regulation and a new aspect of bacterial pathogenicity. Changes in HMod were associated to varying degrees with corresponding gene expression, e. g. depending on chromatin localization and cooperation of the HMod. In summary, infection with Y. enterocolitica remodels HMod in human macrophages to modulate key gene expression programs of the innate immune response.

General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Heinrich-Pette-Institute (HPI), Leibniz Institute for Experimental Virology, Research Group Virus Genomics, Hamburg, Germany. Contributors: Bekere, I., Huang, J., Schnapp, M., Rudolph, M., Berneking, L., Ruckdeschel, K., Grundhoff, A., Günther, T., Fischer, N., Aepfelbacher, M. Publication date: 11.2021 REQUIRED: Peer-reviewed: Yes Publication information Journal: PLOS PATHOG Volume: 17 Issue number: 11 Article number: e1010074 ISSN (Print): 1553-7366 Ratings: Scopus rating (2021): CiteScore 10.5 SJR 2.596 SNIP 1.618 Web of Science (2021): Journal Impact Factor 7.464 UKE base score (2021): Rating 22.723 Original language: English DOIs: 10.1371/journal.ppat.1010074 Source: PubMed Source ID: 34793580 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

Distinct clonal lineages and within-host diversification shape invasive Staphylococcus epidermidis populations S. epidermidis is a substantial component of the human skin microbiota, but also one of the major causes of nosocomial infection in the context of implanted medical devices. We here aimed to advance the understanding of S. epidermidis genotypes and phenotypes conducive to infection establishment. Furthermore, we investigate the adaptation of individual clonal lines to the infection lifestyle based on the detailed analysis of individual S. epidermidis populations of 23 patients suffering from prosthetic joint infection. Analysis of invasive and colonizing S. epidermidis provided evidence that invasive S. epidermidis are characterized by infection-supporting phenotypes (e.g. increased biofilm formation, growth in nutrient poor media and antibiotic resistance), as well as specific genetic traits. The discriminating gene loci were almost exclusively assigned to the mobilome. Here, in addition to IS256 and SCCmec, chromosomally integrated phages was identified for the first time. These phenotypic and genotypic features were more likely present in isolates belonging to sequence type (ST) 2. By comparing seven patient-matched nasal and invasive S. epidermidis isolates belonging to identical genetic lineages, infection-associated phenotypic and genotypic changes were documented. Besides increased biofilm production, the invasive isolates were characterized by better growth in nutrient-poor media and reduced hemolysis. By examining several colonies grown in parallel from each infection, evidence for genetic within-host population heterogeneity was obtained. Importantly, subpopulations carrying IS insertions in agrC, mutations in the acetate kinase (AckA) and deletions in the SCCmec element emerged in several infections. In summary, these results shed light on the multifactorial processes of infection adaptation and demonstrate how S. epidermidis is able to flexibly repurpose and edit factors important for colonization to facilitate survival in hostile infection environments.

General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Bioinformatik Core, Institute of Medical Biometry and Epidemiology, UKE Microscopy Imaging Facility, HELIOS ENDO-Klinik Hamburg, Hamburg – Germany., German National Reference Laboratory for Multidrug-Resistant Gram-negative Bacteria, Department of Medical Microbiology, Ruhr-University Bochum, Universitätsstraße 150, Bochum 44801, Germany. Contributors: Both, A., Huang, J., Qi, M., Lausmann, C., Weißelberg, S., Büttner, H., Lezius, S., Failla, A. V., Christner, M., Stegger, M., Gehrke, T., Baig, S., Citak, M., Alawi, M., Aepfelbacher, M., Rohde, H. Pages: e1009304 Publication date: 02.2021 REQUIRED: Peer-reviewed: Yes Early online date: 05.02.2021 Publication information Journal: PLOS PATHOG Volume: 17 Issue number: 2 ISSN (Print): 1553-7366 Ratings: Scopus rating (2021): CiteScore 10.5 SJR 2.596 SNIP 1.618 Web of Science (2021): Journal Impact Factor 7.464 UKE base score (2021): Rating 22.723 Original language: English DOIs: 10.1371/journal.ppat.1009304 Source: PubMed Source ID: 33544760 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

Benchmark of thirteen bioinformatic pipelines for metagenomic virus diagnostics using datasets from clinical samples INTRODUCTION: Metagenomic sequencing is increasingly being used in clinical settings for difficult to diagnose cases. The performance of viral metagenomic protocols relies to a large extent on the bioinformatic analysis. In this study, the European Society for Clinical Virology (ESCV) Network on NGS (ENNGS) initiated a benchmark of metagenomic pipelines currently used in clinical virological laboratories.

METHODS: Metagenomic datasets from 13 clinical samples from patients with encephalitis or viral respiratory infections characterized by PCR were selected. The datasets were analyzed with 13 different pipelines currently used in virological diagnostic laboratories of participating ENNGS members. The pipelines and classification tools were: Centrifuge, DAMIAN, DIAMOND, DNASTAR, FEVIR, Genome Detective, Jovian, MetaMIC, MetaMix, One Codex, RIEMS, VirMet, and Taxonomer. Performance, characteristics, clinical use, and user-friendliness of these pipelines were analyzed.

RESULTS: Overall, viral pathogens with high loads were detected by all the evaluated metagenomic pipelines. In contrast, lower abundance pathogens and mixed infections were only detected by 3/13 pipelines, namely DNASTAR, FEVIR, and MetaMix. Overall sensitivity ranged from 80% (10/13) to 100% (13/13 datasets). Overall positive predictive value ranged from 71-100%. The majority of the pipelines classified sequences based on nucleotide similarity (8/13), only a minority used amino acid similarity, and 6 of the 13 pipelines assembled sequences de novo. No clear differences in performance were detected that correlated with these classification approaches. Read counts of target viruses varied between the pipelines over a range of 2-3 log, indicating differences in limit of detection.

CONCLUSION: A wide variety of viral metagenomic pipelines is currently used in the participating clinical diagnostic laboratories. Detection of low abundant viral pathogens and mixed infections remains a challenge, implicating the need for standardization and validation of metagenomic analysis for clinical diagnostic use. Future studies should address the selective effects due to the choice of different reference viral databases.

General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands; Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands., Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health and Histopathology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK., Division of Surgery and Intervention Science, University College London, London, United Kingdom; Department of Urology, University College London Hospital, London, United Kingdom; Department of Uro-oncology, University College London Hospital NHS Foundation Trust, London, United Kingdom., Department of Neurology, Erasmus MC University Medical Center, Rotterdam, Netherlands; Department of Radiology, Erasmus MC University Medical Center, Rotterdam, Netherlands; Department of Radiology, Academic Medical Center, Amsterdam, Netherlands., Dokuz Eylul University, University Hospital Henri Mondor (APHP), Laboratory of Clinical and Epidemiological Virology (Rega Institute), Zurich Center for Integrative Human Physiology, Zurich, Switzerland; Institute of Anatomy, University of Zurich, Zurich, Switzerland; Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland., Division of Infectious Diseases, University Hospitals of Geneva, Geneva, Switzerland; Infection Control Programme, University Hospitals of Geneva, Geneva, Switzerland; Centre for Vaccinology, University Hospitals of Geneva, Geneva, Switzerland., Head Reference Laboratory for Neonatal Screening, Center for Health Protection, National Institute for Public Health and the Environment (RIVM), P. O. Box 1, 3720 BA Bilthoven, The Netherlands., Institute of Infectious Diseases, Friedrich-Loeffler Institute, Greifswald-Insel Riems, Germany, SIB Swiss Institute of Bioinformatics, Centre Medical Universitaire, 1 rue Michel Servet, 1211 Geneva 4, Switzerland., Aristotle University of Thessaloniki, Thessaloniki, Greece, Interuniversity Research Institute for Molecular Recognition and Technological Development (IDM), University of Valencia, Polytechnic University of Valencia, Valencia, Spain. Contributors: de Vries, J. J. C., Brown, J. R., Fischer, N., Sidorov, I. A., Morfopoulou, S., Huang, J., Munnink, B. B. O., Sayiner, A., Bulgurcu, A., Rodriguez, C., Gricourt, G., Keyaerts, E., Beller, L., Bachofen, C., Kubacki, J., Samuel, C., Florian, L., Dennis, S., Beer, M., Hoeper, D., Huber, M., Kufner, V., Zaheri, M., Lebrand, A., Papa, A., van Boheemen, S., Kroes, A. C. M., Breuer, J., Lopez-Labrador, F. X., Claas, E. C. J., ESCV Network on Next-Generation Sequencing Publication date: 08.2021 REQUIRED: Peer-reviewed: Yes Publication information Journal: J CLIN VIROL Volume: 141 Article number: 104908 ISSN (Print): 1386-6532 Ratings: Scopus rating (2021): CiteScore 13.6 SJR 3.355 SNIP 2.638 Web of Science (2021): Journal Impact Factor 14.481 UKE base score (2021): Rating 8.665 Original language: English DOIs: 10.1016/j.jcv.2021.104908 Comment Deanary Copyright © 2021. Published by Elsevier B.V.

Source: PubMed Source ID: 34273858 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

Strong Replication Interference Between Hepatitis Delta Viruses in Human Liver Chimeric Mice Background: Hepatitis D Virus (HDV) is classified into eight genotypes with distinct clinical outcomes. Despite the maintenance of highly conserved functional motifs, it is unknown whether sequence divergence between genotypes, such as HDV-1 and HDV-3, or viral interference mechanisms may affect co-infection in the same host and cell, thus hindering the development of HDV inter-genotypic recombinants. We aimed to investigate virological differences of HDV-1 and HDV-3 and assessed their capacity to infect and replicate within the same liver and human hepatocyte in vivo.

Methods: Human liver chimeric mice were infected with hepatitis B virus (HBV) and with one of the two HDV genotypes or with HDV-1 and HDV-3 simultaneously. In a second set of experiments, HBV-infected mice were first infected with HDV-1 and after 9 weeks with HDV-3, or vice versa. Also two distinct HDV-1 strains were used to infect mice simultaneously and sequentially. Virological parameters were determined by strain-specific qRT-PCR, RNA in situ hybridization and immunofluorescence staining.

Results: HBV/HDV co-infection studies indicated faster spreading kinetics and higher intrahepatic levels of HDV-3 compared to HDV-1. In mice that simultaneously received both HDV strains, HDV-3 became the dominant genotype. Interestingly, antigenomic HDV-1 and HDV-3 RNA were detected within the same liver but hardly within the same cell. Surprisingly, sequential super-infection experiments revealed a clear dominance of the HDV strain that was inoculated first, indicating that HDV-infected cells may acquire resistance to super-infection.

Conclusion: Infection with two largely divergent HDV genotypes could be established in the same liver, but rarely within the same hepatocyte. Sequential super-infection with distinct HDV genotypes and even with two HDV-1 isolates was strongly impaired, suggesting that virus interference mechanisms hamper productive replication in the same cell and hence recombination events even in a system lacking adaptive immune responses.

General information Publication status: Published Organisations: I. Medical Clinic and Polyclinic, Institute of Medical Microbiology, Virology and Hygiene, Institut National de la Transfusion Sanguine, Paris, France., Georgetown University Medical Center, Washington, USA., German Centre for Infection Research (DZIF), partner site Hamburg-Luebeck-Borstel, Hamburg, Germany. Contributors: Giersch, K., Hermanussen, L., Volz, T., Volmari, A., Allweiss, L., Sureau, C., Casey, J., Huang, J., Fischer, N., Lütgehetmann, M., Dandri, M. Pages: 671466 Publication date: 2021 REQUIRED: Peer-reviewed: Yes Publication information Journal: FRONT MICROBIOL Volume: 12 ISSN (Print): 1664-302X Ratings: Scopus rating (2021): CiteScore 8.2 SJR 1.314 SNIP 1.497 UKE base score (2021): Rating 16.24 Original language: English DOIs: 10.3389/fmicb.2021.671466 Comment Deanary Copyright © 2021 Giersch, Hermanussen, Volz, Volmari, Allweiss, Sureau, Casey, Huang, Fischer, Lütgehetmann and Dandri.

Source: PubMed Source ID: 34305837 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

Simulation of Folding Kinetics for Aligned RNAs Studying the folding kinetics of an RNA can provide insight into its function and is thus a valuable method for RNA analyses. Computational approaches to the simulation of folding kinetics suffer from the exponentially large folding space that needs to be evaluated. Here, we present a new approach that combines structure abstraction with evolutionary conservation to restrict the analysis to common parts of folding spaces of related RNAs. The resulting algorithm can recapitulate the folding kinetics known for single RNAs and is able to analyse even long RNAs in reasonable time. Our program RNAliHiKinetics is the first algorithm for the simulation of consensus folding kinetics and addresses a long-standing problem in a new and unique way. General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Institute of Biochemical Engineering, Computational Biology group, University of Stuttgart, Allmandring 31, 70569 Stuttgart Contributors: Huang, J., Voß, B. Publication date: 26.02.2021 REQUIRED: Peer-reviewed: Yes Publication information Journal: GENES-BASEL Volume: 12 Issue number: 3 Article number: 347 ISSN (Print): 2073-4425 Ratings: Scopus rating (2021): CiteScore 5 SJR 1.032 SNIP 1.042 Web of Science (2021): Journal Impact Factor 4.141 UKE base score (2021): Rating 12.522 Original language: English DOIs: https://doi.org/10.3390/genes12030347 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

Complete genome sequencing and molecular characterization of SARS-COV-2 from COVID-19 cases in Alborz province in Iran Iran was among countries which was hard hit at the early stage of the coronavirus disease 2019 (COVID-19) pandemic and dealt with the second wave of the pandemic in May and June 2020; however, there are a very limited number of complete genome sequences of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from Iran. In this study, complete genome sequences of the virus in the samples obtained from three patients in Alborz province in May and June 2020 were generated and analyzed using bioinformatic methods. The sequenced genomes were positioned in a cluster with B.4 lineage along with the sequences from other countries namely, United Arab Emirates and Oman. There were seven single nucleotide variations (SNVs) in common in all samples and only one of the sequenced genomes showed the D614G amino acid substitution. Three SNVs, 1397 G > A, 28688T > C, 29742 G > T, which had already been reported in February, were found with high frequency in all the sequenced genomes in this study, implying that viral diversity reflected in the early stages of viral transmission in Iran were established in the second wave. Considering the importance of molecular epidemiology in response to ongoing pandemic, there is an urgent need for more complete genome sequencing and comprehensive analyses to gain insight into the transmission, adaptation and evolution of the virus in Iran.

General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Agricultural Research Education and Extension Organization (AREEO), Razi Vaccine and Serum Research Institute, Karaj, Iran, Alborz University of Medical Sciences Contributors: Kaffashi, A., Huang, J., Bairami, A., Fallah Mehrabadi, M. H., Yaslianifard, S., Bashashati, M., Banihashemi, S. R., Soleimanifar, F., Lotfi, M., Taghizadeh, M., Soleimani, A., Khorasani, A., Moshiri, F., Mozhgani, S. Publication date: 17.09.2021 REQUIRED: Peer-reviewed: Yes Publication information Journal: HELIYON Volume: 7 Issue number: 9 Article number: e08027 ISSN (Print): 2405-8440 Ratings: Scopus rating (2021): CiteScore 4 SJR 0.55 SNIP 1.27 Web of Science (2021): Journal Impact Factor 3.776 UKE base score (2021): Rating 2 Original language: English DOIs: 10.1016/j.heliyon.2021.e08027 Comment Deanary © 2021 The Authors.

Source: PubMed Source ID: 34549097 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

An inter‑laboratory study to investigate the impact of the bioinformatics component on microbiome analysis using mock communities Despite the advent of whole genome metagenomics, targeted approaches (such as 16S rRNA gene amplicon sequencing) continue to be valuable for determining the microbial composition of samples. Amplicon microbiome sequencing can be performed on clinical samples from a normally sterile site to determine the aetiology of an infection (usually single pathogen identification) or samples from more complex niches such as human mucosa or environmental samples where multiple microorganisms need to be identified. The methodologies are frequently applied to determine both presence of micro-organisms and their quantity or relative abundance. There are a number of technical steps required to perform microbial community profiling, many of which may have appreciable precision and bias that impacts final results. In order for these methods to be applied with the greatest accuracy, comparative studies across different laboratories are warranted. In this study we explored the impact of the bioinformatic approaches taken in different laboratories on microbiome assessment using 16S rRNA gene amplicon sequencing results. Data were generated from two mock microbial community samples which were amplified using primer sets spanning five different variable regions of 16S rRNA genes. The PCR-sequencing analysis included three technical repeats of the process to determine the repeatability of their methods. Thirteen laboratories participated in the study, and each analysed the same FASTQ files using their choice of pipeline. This study captured the methods used and the resulting sequence annotation and relative abundance output from bioinformatic analyses. Results were compared to digital PCR assessment of the absolute abundance of each target representing each organism in the mock microbial community samples and also to analyses of shotgun metagenome sequence data. This ring trial demonstrates that the choice of bioinformatic analysis pipeline alone can result in different estimations of the composition of the microbiome when using 16S rRNA gene amplicon sequencing data. The study observed differences in terms of both presence and abundance of organisms and provides a resource for ensuring reproducible pipeline development and application. The observed differences were especially prevalent when using custom databases and applying high stringency operational taxonomic unit (OTU) cut-off limits. In order to apply sequencing approaches with greater accuracy, the impact of different analytical steps needs to be clearly delineated and solutions devised to harmonise microbiome analysis results.

General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Molecular Biology, National Measurement Laboratory, LGC, Department of Microbiology, Virology and Infection Control, Great Ormond Street Hospital for Children NHS Trust, Department of Infection, Immunity and Inflammation, UCL Great Ormond Street Institute of Child Health and Reubens Centre of Paediatric Virology and Metagenomics, Department of Bacteriology, TDI, National Institute for Biological Standards and Control, School of Biosciences, Cardiff University, Wales, UK, Pathogens and Microbes, Wellcome Sanger Institute, Wellcome Genome Campus, Department of Health System Management, School of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, Medical Microbiology Research Laboratory, Bob Champion Research and Educational Building, University of East Anglia, Norwich NR4 7UQ, Department of Biological and Geographical Sciences, School of Applied Sciences, University of Huddersfield, Huddersfield HD1 3DH, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT Contributors: O’Sullivan, D., Doyle, R., Temisak, S., Redshaw, N., Whale, A., Logan, G., Huang, J., Fischer, N., Amos, G., Preston, M., Marchesi, J., Wagner, J., Parkhill, J., Motro, Y., Denise, H., Finn, R., Kay, G., O’Grady, J., Ransom-Jones, E., Wu, H., Laing, E., Benavente, E., Phelan, J., Clark , T., Moran-Gilad, J., Huggett, J. Pages: 10590 Publication date: 19.05.2021 REQUIRED: Peer-reviewed: Yes Publication information Journal: SCI REP-UK Volume: 11 Issue number: 1 ISSN (Print): 2045-2322 Ratings: Scopus rating (2021): CiteScore 6.9 SJR 1.005 SNIP 1.389 Web of Science (2021): Journal Impact Factor 4.996 UKE base score (2021): Rating 17.274 Original language: English DOIs: 10.1038/s41598-021-89881-2 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

SARS Coronavirus-2 variant tracing within the first Coronavirus Disease 19 clusters in northern Germany OBJECTIVES: Investigation whether in depth characterization of virus variant patterns can be used for epidemiological analysis of the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection clusters in Hamburg, Germany.

METHODS: Metagenomic RNA-sequencing and amplicon-sequencing and subsequent variant calling in 25 respiratory samples from SARS-CoV-2 infected patients involved in the earliest infection clusters in Hamburg.

RESULTS: Amplikon sequencing and cluster analyses of these SARS-CoV-2 sequences allowed the identification of the first infection cluster and five non-related infection clusters occurring at the beginning of the viral entry of SARS-CoV-2 in the Hamburg metropolitan region. Viral genomics together with epidemiological analyses revealed that the index patient acquired the infection in northern Italy and transmitted it to two out of 134 contacts. Single nucleotide polymorphisms clearly distinguished the virus variants of the index and other clusters and allowed us to track in which sequences worldwide these mutations were first described. Minor variant analyses identified the transmission of intra-host variants in the index cluster and household clusters.

CONCLUSIONS: SARS-CoV-2 variant tracing allows the identification of infection clusters and the follow up of infection chains occurring in the population. Furthermore, the follow up of minor viral variants in infection clusters can provide further resolution on transmission events indistinguishable at a consensus sequence level.

General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, I. Medical Clinic and Polyclinic, Department of Pediatrics, Department of Intensive Care, Department of Diagnostic and Interventional Radiology and Nuclear Medicine, Heinrich-Pette-Institute (HPI), Leibniz Institute for Experimental Virology, Research Group Virus Genomics, Hamburg, Germany., Bernhard Nocht Institute, Leibniz Institute for Tropical Medicine, Hamburg, Germany. Contributors: Pfefferle, S., Günther, T., Kobbe, R., Czech-Sioli, M., Nörz, D., Santer, R., Oh, J., Kluge, S., Oestereich, L., Peldschus, K., Indenbirken, D., Huang, J., Grundhoff, A., Aepfelbacher, M., Knobloch, J. K., Lütgehetmann, M., Fischer, N. Pages: 130.e5-130.e8 Publication date: 01.2021 REQUIRED: Peer-reviewed: Yes Early online date: 29.09.2020 Publication information Journal: CLIN MICROBIOL INFEC Volume: 27 Issue number: 1 ISSN (Print): 1198-743X Ratings: Scopus rating (2021): CiteScore 16.5 SJR 3.111 SNIP 3.017 Web of Science (2021): Journal Impact Factor 13.31 UKE base score (2021): Rating 23.021 Original language: English DOIs: 10.1016/j.cmi.2020.09.034 Comment Deanary Copyright © 2020. Published by Elsevier Ltd.

Source: PubMed Source ID: 33007476 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

Vertically transferred maternal immune cells promote neonatal immunity against early life infections During mammalian pregnancy, immune cells are vertically transferred from mother to fetus. The functional role of these maternal microchimeric cells (MMc) in the offspring is mostly unknown. Here we show a mouse model in which MMc numbers are either normal or low, which enables functional assessment of MMc. We report a functional role of MMc in promoting fetal immune development. MMc induces preferential differentiation of hematopoietic stem cells in fetal bone marrow towards monocytes within the myeloid compartment. Neonatal mice with higher numbers of MMc and monocytes show enhanced resilience against cytomegalovirus infection. Similarly, higher numbers of MMc in human cord blood are linked to a lower number of respiratory infections during the first year of life. Our data highlight the importance of MMc in promoting fetal immune development, potentially averting the threats caused by early life exposure to pathogens.

General information Publication status: Published Organisations: Department of Obstetrics and Fetal Medicine, Institute of Developmental Neurophysiology, Department of Stem Cell Transplantation, Bioinformatik Core, Institute of Medical Microbiology, Virology and Hygiene, Institute of Clinical Chemistry and Laboratory Medicine, Institute for Immunology Contributors: Stelzer, I., Urbschat, C., Schepanski, S., Thiele, K., Triviai, I., Wieczorek, A., Alawi, M., Ohnezeit, D., Kottlau, J., Huang, J., Fischer, N., Mittrücker, H., Solano, M. E., Fehse, B., Diemert, A., Stahl, F., Arck, P. Pages: 4706 Publication date: 04.08.2021 REQUIRED: Peer-reviewed: Yes Publication information Journal: NAT COMMUN Volume: 12 Issue number: 1 ISSN (Print): 2041-1723 Ratings: Scopus rating (2021): CiteScore 23.2 SJR 4.846 SNIP 3.341 Web of Science (2021): Journal Impact Factor 17.694 UKE base score (2021): Rating 58.852 Original language: English DOIs: 10.1038/s41467-021-24719-z Comment Deanary © 2021. The Author(s).

Source: PubMed Source ID: 34349112 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

1.3. 2020 Complete Genome Sequence of a SARS-CoV-2 Strain Isolated in Northern Germany Here, we describe the complete genome sequence of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain isolated from an oropharyngeal swab sample from a female patient with COVID-19 who was infected in Hamburg, northern Germany.

General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Heinrich Pette Institute, Leibniz Institute for Experimental Virology , Hamburg , Germany., Bernhard Nocht Institute, Leibniz Institute for Tropical Medicine, Hamburg, Germany. Contributors: Pfefferle, S., Huang, J., Nörz, D., Indenbirken, D., Lütgehetmann, M., Oestereich, L., Günther, T., Grundhoff, A., Aepfelbacher, M., Fischer, N. Publication date: 04.06.2020 REQUIRED: Peer-reviewed: Yes Publication information Journal: MICROBIOL RESOUR ANN Volume: 9 Issue number: 23 ISSN (Print): 2576-098X Ratings: Scopus rating (2020): CiteScore 1.5 SJR 0.383 SNIP 0.319 UKE base score (2020): Rating 2 Original language: English DOIs: 10.1128/MRA.00520-20 DOI: 10.1128/MRA.00520-20 Comment Deanary Copyright © 2020 Pfefferle et al.

Source: PubMed Source ID: 32499358 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

1.4. 2019 T-lymphocyte-specific knockout of IKK-2 or NEMO induces T17 cells in an experimental nephrotoxic nephritis mouse model Experimental nephrotoxic serum nephritis (NTN) is a model for T-cell-mediated human rapid progressive glomerulonephritis. T-cell receptor stimulation involves intracellular signaling events that ultimately lead to the activation of transcription factors, such as NF-κB. We explored the involvement of the NF-κB components IKK-2 and NEMO in NTN, by using cell-specific knockouts of IKK-2 and NEMO in CD4+ T lymphocytes. Our results demonstrate that although the course of disease was not grossly altered in CD4xIKK2Δ and CD4xNEMOΔ animals, renal regulatory T cells were significantly reduced and T helper (Th)1 and Th17 cells significantly increased in both knockout mouse groups. The expression of the renal cytokines and chemokines IL-1β, CCL-2, and CCL-20 was also significantly altered in both knockout mice. Lymphocyte transcriptome analysis confirmed the increased expression of Th17-related cytokines in spleen CD4+ T cells. Moreover, our array data demonstrate an interrupted canonical NF-κB pathway and an increased expression of noncanonical NF-κB pathway-related genes in nephritic CD4xNEMOΔ mice, highlighting different downstream effects of deletion of IKK-2 or NEMO in T lymphocytes. We propose that better understanding of the role of IKK-2 and NEMO in nephritis is essential for the clinical application of kinase inhibitors in patients with glomerulonephritis.-Guo, L., Huang, J., Chen, M., Piotrowski, E., Song, N., Zahner, G., Paust, H.-J., Alawi, M., Geffers, R., Thaiss, F. T-lymphocyte-specific knockout of IKK-2 or NEMO induces Th17 cells in an experimental nephrotoxic nephritis mouse model.

General information Publication status: Published Organisations: III. Department of Medicine, Institute of Medical Microbiology, Virology and Hygiene, Bioinformatik Core, Heinrich-Pette-Institute (HPI), Leibniz Institute for Experimental Virology, Research Group Virus Genomics, Hamburg, Germany., Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany. Contributors: Guo, L., Huang, J., Chen, M., Piotrowski, E., Song, N., Zahner, G., Paust, H., Alawi, M., Geffers, R., Thaiss, F. REQUIRED books only: Number of pages: 13 Pages: 2359-2371 Publication date: 02.2019 REQUIRED: Peer-reviewed: Yes Early online date: 04.10.2018 Publication information Journal: FASEB J Volume: 33 Issue number: 2 ISSN (Print): 0892-6638 Ratings: Scopus rating (2019): CiteScore 5.6 SJR 1.866 SNIP 1.137 Web of Science (2019): Journal Impact Factor 4.966 UKE base score (2019): Rating 21.646 Original language: English DOIs: 10.1096/fj.201800485RR Source: PubMed Source ID: 30285578 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

Changes in the composition of the upper respiratory tract microbial community in granulomatosis with polyangiitis Dysbiosis¸ i.e. changes in microbial composition at a mucosal interface, is implicated in the pathogenesis of many chronic inflammatory and autoimmune diseases. To assess the composition of the microbial upper respiratory tract (URT) community in patients with granulomatosis with polyangiitis (GPA), we used culture-independent high-throughput methods. In this prospective clinical study, nasal swabs were collected from patients with GPA, patients with rheumatoid arthritis (RA, disease control), and healthy controls. Nasal bacterial taxa were assessed using V3-V4 region 16S rRNA amplicon sequencing. Staphylococcus aureus, Haemophilus influenza, and entero- and rhinoviruses were detected using qPCR. Unbiased metagenomic RNA sequencing (UMERS) was performed in a subset of samples to determine the relative abundance of bacterial, fungal, and viral species. A trend toward reduced microbiome diversity was detected in GPA samples compared with healthy controls. The abundance of bacterial taxa and microbial richness were significantly decreased in GPA samples compared with RA samples. The relative abundance of bacterial families shifted, with increased Planococcaceae and decreased Moraxellaceae, Tissierellaceae, Staphylococcaceae, and Propionibacteriaceae in GPA and RA. Further, decreased abundance of Corynebacteriaceae, and Aerococcaceae was observed in GPA samples. Significantly more colonization of S. aureus was seen in the nasal microbiome of GPA compared with RA and healthy control samples. H. influenzae colonization was also observed in GPA samples. UMERS detected the presence of rhinoviral sequences in some GPA samples. Thus, our study uncovered changes in the URT microbial composition in patients with GPA and RA, suggesting that both immunosuppression and disease background affect the URT microbiome. Complex alterations of host-microbiome interactions in the URT could influence chronic endonasal inflammation in GPA.

General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, III. Department of Medicine, Department of Rheumatology & Clinical Immunology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany. Electronic address: peter.lamprecht@uksh.de., Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Martinistrasse 46, 20246, Hamburg, Germany; German Center for Research on Infection, partner site Hamburg-Borstel-Lübeck-Riems, Germany. Electronic address: nfischer@uke.de., Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Martinistrasse 46, 20246, Hamburg, Germany. Electronic address: j.huang@uke.de., Heinrich-Pette Institute, Leibniz Institute for Experimental Virology, Martinistrasse 52, 20252, Hamburg, Germany. Electronic address: lia.burkhardt@hpi.uni-hamburg.de., Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Martinistrasse 46, 20246, Hamburg, Germany. Electronic address: m.luetgehetmann@uke.de., Department of Rheumatology and Immunology, Klinikum Bad Bramstedt, Oskar-Alexander-Strasse 26, 24576, Bad Bramstedt, Germany. Electronic address: fabian.arndt@klinikumbb.de., Department of Otorhinolaryngology, Head and Neck Surgery, University of Kiel, Arnold-Heller-Strasse 3, Haus 27, 24105, Kiel, Germany. Electronic address: ida.rolfs@web.de., Department of Rheumatology & Clinical Immunology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany. Electronic address: anja.kerstein@uksh.de., Department of Nephrology and Rheumatology, Medicine III, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. Electronic address: c.iking-konert@uke.de., Department of Otorhinolaryngology, Head and Neck Surgery, University of Kiel, Arnold-Heller-Strasse 3, Haus 27, 24105, Kiel, Germany. Electronic address: laudien@hno.uni-kiel.de. Contributors: Lamprecht, P., Fischer, N., Huang, J., Burkhardt, L., Lütgehetmann, M., Arndt, F., Rolfs, I., Kerstein, A., Iking-Konert, C., Laudien, M. REQUIRED books only: Number of pages: 11 Pages: 29-39 Publication date: 02.2019 REQUIRED: Peer-reviewed: Yes Publication information Journal: J AUTOIMMUN Volume: 97 ISSN (Print): 0896-8411 Ratings: Scopus rating (2019): CiteScore 11.7 SJR 2.107 SNIP 1.56 Web of Science (2019): Journal Impact Factor 6.658 UKE base score (2019): Rating 23.594 Original language: English DOIs: 10.1016/j.jaut.2018.10.005 Comment Deanary Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Source: PubMed Source ID: 30420263 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

1.5. 2017 Emergence of ceftazidime/avibactam non-susceptibility in an MDR Klebsiella pneumoniae isolate Background: Avibactam is a novel broad-range β-lactamase inhibitor active against Ambler class A (including ESBL and KPC) and some Ambler class C and D (e.g. OXA-48) enzymes. We here report on the emergence of ceftazidime/avibactam resistance in clinical, multiresistant, OXA-48 and CTX-M-14-producing Klebsiella pneumoniae isolate DT12 during ceftazidime/avibactam treatment.

Methods and results: Comparative whole-genome sequence analysis identified two SNPs in the CTX-M-14-encoding gene leading to two amino acid changes (P170S and T264I). Compared with WT CTX-M-14, expression of the CTX-M-14 Δ170Δ264 isoform in Escherichia coli led to a >64- and 16-fold increase in ceftazidime and ceftazidime/avibactam MICs, respectively, functionally linking the observed SNPs and elevated MICs. The mutated CTX-M-14 isoform exhibited augmented ceftazidime hydrolytic activity, which was a reasonable cause for impaired susceptibility to avibactam inhibition. The P170S exchange in CTX-M-14 was found in association with elevated ceftazidime/avibactam MICs for independent K. pneumoniae isolates, but was not sufficient for full resistance. Apparently, additional CTX-M-independent mechanisms contribute to ceftazidime/avibactam resistance in K. pneumoniae DT12.

Conclusions: This study on the molecular basis of ceftazidime/avibactam resistance in clinical K. pneumoniae emerging in vivo underscores the need for continuous monitoring of ceftazidime/avibactam susceptibility during therapy. Despite sustained inhibition of OXA-48, rapid development of CTX-M-14 isoforms exhibiting augmented ceftazidime hydrolytic activity may limit the usefulness of ceftazidime/avibactam monotherapies in infections caused by isolates carrying bla CTX-M-14 and bla OXA-48 .

General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Department of Intensive Care, DESY, Lab Struct Biol Infect & Inflammat, Notkestr 85,Bldg 22a, D-22603 Hamburg, Germany Contributors: Both, A., Büttner, H., Huang, J., Perbandt, M., Belmar Campos, C., Christner, M., Maurer, F. P., Kluge, S., König, C., Aepfelbacher, M., Wichmann, D., Rohde, H. Pages: 2483-2488 Publication date: 01.09.2017 REQUIRED: Peer-reviewed: Yes Publication information Journal: J ANTIMICROB CHEMOTH Volume: 72 Issue number: 9 ISSN (Print): 0305-7453 Ratings: Scopus rating (2017): CiteScore 8.7 SJR 2.419 SNIP 1.584 Web of Science (2017): Journal Impact Factor 5.217 UKE base score (2017): Rating 20.496 Original language: English DOIs: 10.1093/jac/dkx179 Source: PubMed Source ID: 28637339 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

1.6. 2016 First report of Escherichia coli co-producing NDM-1 and OXA-232 Recently Gram-negative bacteria co-producing multiple carbapenemases have emerged in different parts of the world. We report the first isolation of an Escherichia coli strain co-producing the carbapenemases NDM-1 and OXA-232.

General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Institute of Hygiene and Microbiology, Department of Microbiology, Universitätsstrasse 150, 44801 Bochum, Germany., Schoen Klinik Hamburg Eilbek, Neurozentrum, Dehnheide 120, 22081 Hamburg, Germany., MVZ Labor Dr. Fenner und Kollegen, Bergstrasse 14, 20095 Hamburg, Germany., Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistraße 52, 20251 Hamburg, Germany., MVZ Labor Dr. Fenner und Kollegen, Bergstrasse 14, 20095 Hamburg, Germany. Electronic address: mhentschke@fennerlabor.de. Contributors: Both, A., Huang, J., Kaase, M., Hezel, J., Wertheimer, D., Fenner, I., Günther, T., Grundhoff, A., Büttner, H., Aepfelbacher, M., Rohde, H., Hentschke, M. REQUIRED books only: Number of pages: 2 Pages: 437-438 Publication date: 12.2016 REQUIRED: Peer-reviewed: Yes Publication information Journal: DIAGN MICR INFEC DIS Volume: 86 Issue number: 4 ISSN (Print): 0732-8893 Ratings: Scopus rating (2016): CiteScore 4.8 SJR 1.237 SNIP 1.055 Web of Science (2016): Journal Impact Factor 2.401 UKE base score (2016): Rating 9.867 Original language: English DOIs: 10.1016/j.diagmicrobio.2016.09.005 Comment Deanary Hentschke ohne UKE-Affiliierung

Source: PubMed Source ID: 27681362 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

Autoimmune Renal Disease Is Exacerbated by S1P-Receptor-1-Dependent Intestinal Th17 Cell Migration to the Kidney Th17 cells are most abundant in the gut, where their presence depends on the intestinal microbiota. Here, we examined whether intestinal Th17 cells contribute to extra-intestinal Th17 responses in autoimmune kidney disease. We found high frequencies of Th17 cells in the kidneys of patients with antineutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis. We utilized photoconversion of intestinal cells in Kaede mice to track intestinal T cell mobilization upon glomerulonephritis induction, and we found that Th17 cells egress from the gut in a S1P-receptor-1-dependent fashion and subsequently migrate to the kidney via the CCL20/CCR6 axis. Depletion of intestinal Th17 cells in germ-free and antibiotic-treated mice ameliorated renal disease, whereas expansion of these cells upon Citrobacter rodentium infection exacerbated pathology. Thus, in some autoimmune settings, intestinal Th17 cells migrate into target organs, where they contribute to pathology. Targeting the intestinal Th17 cell “reservoir” may present a therapeutic strategy for these autoimmune disorders.

POM-Newsletter

General information Publication status: Published Organisations: III. Department of Medicine, Institute of Pathology, Institute of Medical Microbiology, Virology and Hygiene, Department of General, Visceral and Thoracic Surgery, Institute for Immunology, I. Medical Clinic and Polyclinic, Philipps-Universität Marburg, Institut für Medizinische Mikrobiologie und Krankenhaushygiene, 35043 Marburg, Germany., The Francis Crick Institute, Midland Road, London NW1 1AT, UK. Contributors: Krebs, C. F., Paust, H., Krohn, S., Koyro, T., Brix, S. R., Riedel, J., Bartsch, P., Wiech, T., Meyer-Schwesinger, C., Huang, J., Fischer, N., Busch, C. P., Mittrücker, H., Steinhoff, U., Stockinger, B., Perez, L. G., Wenzel, U. O., Janneck, M., Steinmetz, O. M., Gagliani, N., Stahl, R. A. K., Huber, S., Turner, J., Panzer, U. REQUIRED books only: Number of pages: 15 Pages: 1078-1092 Publication date: 15.11.2016 REQUIRED: Peer-reviewed: Yes Publication information Journal: IMMUNITY Volume: 45 Issue number: 5 ISSN (Print): 1074-7613 Ratings: Scopus rating (2016): CiteScore 40.9 SJR 16.957 SNIP 4.704 Web of Science (2016): Journal Impact Factor 22.845 UKE base score (2016): Rating 85.367 Original language: English DOIs: 10.1016/j.immuni.2016.10.020 Additional files: 1_pom_2016-12-(002) Comment Deanary Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Source: PubMed Source ID: 27851911 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

1.7. 2014 Analysing RNA-kinetics based on folding space abstraction General information Publication status: Published Organisations: Genetics & Experimental Bioinformatics, Institute of Biology III, University Freiburg Contributors: Huang, J., Voß, B. Pages: 60 Publication date: 2014 REQUIRED: Peer-reviewed: Yes Publication information Journal: BMC BIOINFORMATICS Volume: 15 Issue number: 1 ISSN (Print): 1471-2105 Ratings: Scopus rating (2014): CiteScore 5.5 SJR 1.916 SNIP 1.199 Web of Science (2014): Journal Impact Factor 2.576 UKE base score (2014): Rating 14.011 Original language: English DOIs: 10.1186/1471-2105-15-60 Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

1.8. 2012 Abstract folding space analysis based on helices General information Publication status: Published Organisations: Institut für Informatik, University of Freiburg, Genetics & Experimental Bioinformatics, Institute of Biology III, University Freiburg Contributors: Huang, J., Backofen, R., Voß, B. Pages: 2135-2147 Publication date: 2012 REQUIRED: Peer-reviewed: Yes Publication information Journal: RNA Volume: 18 Issue number: 12 ISSN (Print): 1355-8382 Ratings: Scopus rating (2012): CiteScore 9.7 SJR 4.545 SNIP 1.125 Web of Science (2012): Journal Impact Factor 5.088 UKE base score (2012): Rating 17.833 Original language: English Research output: SCORING: Contribution to journal › SCORING: Journal articles › Research › peer-review

Reducing the search space in RNA helix based folding. European Conference on Computational Biology RNA has many pivotal functions especially in the regulation of gene expression by ncRNAs. Identification of their structure is important for understanding their function and often requires a more in-depth analysis of the folding space. Here, the major drawback is the exponential growth of the folding space. Therefore, methods are either limited in the sequence length they can analyze or they make use of heuristics, sampling or abstraction.

With RNAHELICES1, we introduced a position-specific abstraction based on helices which we termed helix index shapes or hishapes for short. Based on this, we developed two methods, one for energy barrier estimation, called HIPATH, and one for abstract structure comparison, termed HITED. Furthermore, we could show the superior performance of HIPATH compared to other existing methods and the competitive accuracy of HITED.

Despite polynomial complexity when returning k-best hishapes, the number of possible hishapes is still exponential. This makes it necessary to reduce the number of hishape classes. By applying two rules (termed Nos and No+) that modify candidate selection during the recursive calculation in Dynamic Programming (DP), we investigate the search space prior to and following the application of both rules. General information Publication status: Published Organisations: Institute of Medical Microbiology, Virology and Hygiene, Genetics & Experimental Bioinformatics, Institute of Biology III, University Freiburg Contributors: Huang, J., Voß, B. Publication date: 09.09.2012 Host publication information Title of host publication: European Conference on Computational Biology (ECCB) 2012 Research output: SCORING: Book or contribution to book/anthology › Conference contribution – Poster › Research

1.9. 2011 RNAHeliCes — Folding space analysis based on position aware structure abstraction General information Publication status: Published Organisations: Genetics & Experimental Bioinformatics, Institute of Biology III, University Freiburg Contributors: Huang, J., Voß, B. Pages: RT–31 Publication date: 2011 Host publication information Title of host publication: In Proceedings of the German Conference on Bioinformatics 2011 Research output: SCORING: Book or contribution to book/anthology › Conference contribution – Article for conference › Research › peer-review

  1. Research outputs Weitere Informationen zu Reports finden Sie im Intranet unter https://intranet.uke.de/fisberichte Ordered by: Year and 1st author

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