This is the institutional Repository of the Helmholtz Centre for Infection Research in Braunschweig/Germany (HZI), the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrücken/Germany, the TWINCORE Zentrum für Exprerimentelle und Klinische Infektionsforschung, Hannover/Germany,Helmholtz-Institut für RNA-basierte Infektionsforschung (HIRI), Braunschweig Integrated Centre for Systems biology (BRICS), Centre for Structural Systems Biology (CSSB) and the Study Centre Hannover, Hannover/Germany.


  • Studies on the biologically active secondary metabolites of the new spider parasitic fungus Gibellula gamsii

    Kuephadungphan, Wilawan; Macabeo, Allan Patrick G.; Luangsa-ard, Janet Jennifer; Tasanathai, Kanoksri; Thanakitpipattana, Donnaya; Phongpaichit, Souwalak; Yuyama, Kamila; Stadler, Marc (Springer, 2018-08-15)
    Numerous gatherings of a new species of the genus Gibellula, closely resembling the monotypic, neotropical G. mirabilis were encountered in Thailand. The taxon was cultured successfully although no in vitro sporulation was observed. The new species, Gibellula gamsii, could be distinguished from closely related other Gibellula species on the basis of morphological features and phylogenetic inferences recruiting concatenated sequences of five DNA loci including ITS, LSU, RPB1, RPB2, and EF1-α. The secondary metabolites of G. gamsii, strain BCC47868, were studied concurrently after preparative separation of the crude extract by preparative high-performance liquid chromatography (HPLC). Two new 1,3-disubstituted β-carboline alkaloids, for which we propose the trivial names, gibellamines A (1) and B (2), were isolated. The chemical structures of these compounds were elucidated by interpretation of spectral data, generated by nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). The alkaloid 1 also exhibited moderate anti-biofilm activity against Staphylococcus aureus.
  • Aurantimycin resistance genes contribute to survival of Listeria monocytogenes during life in the environment.

    Hauf, Samuel; Herrmann, Jennifer; Miethke, Marcus; Gibhardt, Johannes; Commichau, Fabian M; Müller, Rolf; Fuchs, Stephan; Halbedel, Sven; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Wiley-Blackwell, 2019-01-15)
    Bacteria can cope with toxic compounds such as antibiotics by inducing genes for their detoxification. A common detoxification strategy is compound excretion by ATP-binding cassette (ABC) transporters, which are synthesized upon compound contact. We previously identified the multi drug resistance ABC transporter LieAB in Listeria monocytogenes, a Gram-positive bacterium that occurs ubiquitously in the environment, but also causes severe infections in humans upon ingestion. Expression of the lieAB genes is strongly induced in cells lacking the PadR-type transcriptional repressor LftR, but compounds leading to relief of this repression in wild type cells were not known. Using RNA-Seq and promoter-lacZ fusions we demonstrate highly specific repression of the lieAB and lftRS promoters through LftR. Screening of a natural compound library yielded the depsipeptide aurantimycin A - synthesized by the soil-dwelling Streptomyces aurantiacus - as the first known naturally occurring inducer of lieAB expression. Genetic and phenotypic experiments concordantly show that aurantimycin A is a substrate of the LieAB transporter and thus, lftRS and lieAB represent the first known genetic module conferring and regulating aurantimycin A resistance. Collectively, these genes may support the survival of L. monocytogenes when it comes into contact with antibiotic-producing bacteria in the soil. This article is protected by copyright. All rights reserved.
  • Discovery of Leptospira spp. seroreactive peptides using ORFeome phage display.

    Ramli, Siti Roszilawati; Moreira, Gustavo M S G; Zantow, Jonas; Goris, Marga G A; Nguyen, Van Kinh; Novoselova, Natalia; Pessler, Frank; Hust, Michael; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany. (PLOS, 2019-01-01)
    Leptospirosis is the most common zoonotic disease worldwide. The diagnostic performance of a serological test for human leptospirosis is mainly influenced by the antigen used in the test assay. An ideal serological test should cover all serovars of pathogenic leptospires with high sensitivity and specificity and use reagents that are relatively inexpensive to produce and can be used in tropical climates. Peptide-based tests fulfil at least the latter two requirements, and ORFeome phage display has been successfully used to identify immunogenic peptides from other pathogens. Two ORFeome phage display libraries of the entire Leptospira spp. genomes from five local strains isolated in Malaysia and seven WHO reference strains were constructed. Subsequently, 18 unique Leptospira peptides were identified in a screen using a pool of sera from patients with acute leptospirosis. Five of these were validated by titration ELISA using different pools of patient or control sera. The diagnostic performance of these five peptides was then assessed against 16 individual sera from patients with acute leptospirosis and 16 healthy donors and was compared to that of two recombinant reference proteins from L. interrogans. This analysis revealed two peptides (SIR16-D1 and SIR16-H1) from the local isolates with good accuracy for the detection of acute leptospirosis (area under the ROC curve: 0.86 and 0.78, respectively; sensitivity: 0.88 and 0.94; specificity: 0.81 and 0.69), which was close to that of the reference proteins LipL32 and Loa22 (area under the ROC curve: 0.91 and 0.80; sensitivity: 0.94 and 0.81; specificity: 0.75 and 0.75). This analysis lends further support for using ORFeome phage display to identify pathogen-associated immunogenic peptides, and it suggests that this technique holds promise for the development of peptide-based diagnostics for leptospirosis and, possibly, of vaccines against this pathogen.
  • Identification of Cerebrospinal Fluid Metabolites as Biomarkers for Enterovirus Meningitis.

    Ratuszny, Dominica; Sühs, Kurt-Wolfram; Novoselova, Natalia; Kuhn, Maike; Kaever, Volkhard; Skripuletz, Thomas; Pessler, Frank; Stangel, Martin; TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany. (MDPI, 2019-01-15)
    Enteroviruses are among the most common causes of viral meningitis. Enteroviral meningitis continues to represent diagnostic challenges, as cerebrospinal fluid (CSF) cell numbers (a well validated diagnostic screening tool) may be normal in up to 15% of patients. We aimed to identify potential CSF biomarkers for enteroviral meningitis, particularly for cases with normal CSF cell count. Using targeted liquid chromatography-mass spectrometry, we determined metabolite profiles from patients with enteroviral meningitis (n = 10), and subdivided them into those with elevated (n = 5) and normal (n = 5) CSF leukocyte counts. Non-inflamed CSF samples from patients with Bell’s palsy and normal pressure hydrocephalus (n = 19) were used as controls. Analysis of 91 metabolites revealed considerable metabolic reprogramming in the meningitis samples. It identified phosphatidylcholine, asparagine, and glycine as an accurate (AUC, 0.92) combined classifier for enterovirus meningitis overall, and kynurenine as a perfect biomarker for enteroviral meningitis with an increased CSF cell count (AUC, 1.0). Remarkably, alone emerged as a single accurate (AUC, 0.87) biomarker for enteroviral meningitis with normal cell count, and a combined classifier comprising,, and achieved nearly perfect classification (AUC, 0.99). Taken together, this analysis reveals the potential of CSF metabolites as additional diagnostic tools for enteroviral meningitis, and likely other central nervous system (CNS) infections.
  • Demarcated thresholds of tumor-specific CD8 T cells elicited by MCMV-based vaccine vectors provide robust correlates of protection.

    Beyranvand Nejad, Elham; Ratts, Robert B; Panagioti, Eleni; Meyer, Christine; Oduro, Jennifer D; Cicin-Sain, Luka; Früh, Klaus; van der Burg, Sjoerd H; Arens, Ramon; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (BMC, 2019-01-31)
    The capacity of cytomegalovirus (CMV) to elicit long-lasting strong T cell responses, and the ability to engineer the genome of this DNA virus positions CMV-based vaccine vectors highly suitable as a cancer vaccine platform. Defined immune thresholds for tumor protection and the factors affecting such thresholds have not well been investigated in cancer immunotherapy. We here determined using CMV as a vaccine platform whether critical thresholds of vaccine-specific T cell responses can be established that relate to tumor protection, and which factors control such thresholds. We generated CMV-based vaccine vectors expressing the E7 epitope and tested these in preclinical models of HPV16-induced cancer. Vaccination was applied via different doses and routes (intraperitoneal (IP), subcutaneous (SC) and intranasal (IN)). The magnitude, kinetics and phenotype of the circulating tumor-specific CD8 Immunization with CMV-based vaccines via the IP or SC route eliciting vaccine-induced CD8 This study highlight the effectiveness of CMV-based vaccine vectors, and shows that demarcated thresholds of vaccine-specific T cells could be defined that correlate to tumor protection. Together, these results may hold importance for cancer vaccine development to achieve high efficacy in vaccine recipients.

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