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) the Study Centre Hannover, Hannover/Germany and the Centre for Individualised Infection Medicine (CiiM).

 

  • PD-1/PD-L1 pathway inhibition to restore effector functions in exhausted CD8+ T cells: chances, limitations and potential risks

    Veluswamy, Priya; Bruder, Dunja; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (AME Publishing Company, 2018-04)
    T cell exhaustion is a well-known mechanism involved in escape of degenerated cells or certain pathogens from CD8+ T cell-mediated immune surveillance, ultimately resulting in tumor development and chronic infections, respectively. Next to activated T cells, exhausted CD8+ T cells typically express high levels of the programmed cell death-1 (PD-1) receptor. While interaction of PD-1 with its ligand programmed death-ligand 1 (PD-L1) on hemotopoietic and non-hemotopoietic cells is important for the re-establishment of homeostasis following immune activation, PD-1/PD-L1 interaction represents a major drawback in certain other disease settings such as cancer or chronic viral infections. Here PD-1 signalling in T cells prevents efficient anti-tumor or anti-viral immune responses. Thus, therapeutic interference with the PD-1/PD-L1 pathway represents a promising approach for releasing exhausted CD8+ T cells from PD-1-dependent suppression and reactivation of effector functions. However, recent reports have highlighted unexpected outcomes of PD-1/PD-L1 pathway inhibition in the context of chronic infections. We provide here a comprehensive overview of the recent discoveries made in the context of PD-1/PD-L1 checkpoint inhibition that are considered relevant with respect to the targeted reactivation of effector functions in exhausted CD8+ T cells. We briefly discuss the impact of PD-1 signalling on the expression of certain transcription factors, on epigenetic modifications affecting chromatin accessibility, on cellular metabolism and the expression of certain cytokine receptors involved in immune homeostasis. These newly uncovered facts should be carefully considered before further development of therapies targeting the PD-1/PD-L1 pathway that are aiming at the restoration of pathogen-specific and anti-tumor CD8+ T cell effector functions in order to prevent adverse side effects. © 2018, Translational Cancer Research.
  • Structure of heme d-free cd nitrite reductase NirS.

    Klünemann, Thomas; Blankenfeldt, Wulf; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (International Union of Crystallography, 2020-05-29)
    A key step in anaerobic nitrate respiration is the reduction of nitrite to nitric oxide, which is catalysed by the cd1 nitrite reductase NirS in, for example, the Gram-negative opportunistic pathogen Pseudomonas aeruginosa. Each subunit of this homodimeric enzyme consists of a cytochrome c domain and an eight-bladed β-propeller that binds the uncommon isobacteriochlorin heme d1 as an essential part of its active site. Although NirS has been well studied mechanistically and structurally, the focus of previous studies has been on the active heme d1-bound form. The heme d1-free form of NirS reported here, which represents a premature state of the reductase, adopts an open conformation with the cytochrome c domains moved away from each other with respect to the active enzyme. Further, the movement of a loop around Trp498 seems to be related to a widening of the propeller, allowing easier access to the heme d1-binding side. Finally, a possible link between the open conformation of NirS and flagella formation in P. aeruginosa is discussed.
  • Polyketide-Derived Secondary Metabolites from a Dothideomycetes Fungus, . et . ., (Muyocopronales) with Antimicrobial and Cytotoxic Activities.

    Mapook, Ausana; Macabeo, Allan Patrick G; Thongbai, Benjarong; Hyde, Kevin D; Stadler, Marc; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (MDPI, 2020-04-08)
    Pseudopalawania siamensisgen. et sp. nov., from northern Thailand, is introduced based on multi-gene analyses and morphological comparison. An isolate was fermented in yeast malt culture broth and explored for its secondary metabolite production. Chromatographic purification of the crude ethyl acetate (broth) extract yielded four tetrahydroxanthones comprised of a new heterodimeric bistetrahydroxanthone, pseudopalawanone (1), two known dimeric derivatives, 4,4'-secalonic acid D (2) and penicillixanthone A (3), the corresponding monomeric tetrahydroxanthone paecilin B (4), and the known benzophenone, cephalanone F (5). Compounds 1-3 showed potent inhibitory activity against Gram-positive bacteria. Compounds 2 and 3 were inhibitory against Bacillus subtilis with minimum inhibitory concentrations (MIC) of 1.0 and 4.2 μg/mL, respectively. Only compound 2 showed activity against Mycobacterium smegmatis. In addition, the dimeric compounds 1-3 also showed moderate cytotoxic effects on HeLa and mouse fibroblast cell lines, which makes them less attractive as candidates for development of selectively acting antibiotics.
  • 2-Hydroxysorangiadenosine: Structure and Biosynthesis of a Myxobacterial Sesquiterpene-Nucleoside.

    Okoth, Dorothy A; Hug, Joachim J; Garcia, Ronald; Spröer, Cathrin; Overmann, Jörg; Müller, Rolf; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (MDPI, 2020-06-09)
    Myxobacteria represent an under-investigated source for biologically active natural products featuring intriguing structural moieties with potential applications, e.g., in the pharmaceutical industry. Sorangiadenosine and the here-discovered 2-hydroxysorangiadenosine are myxobacterial sesquiterpene-nucleosides with an unusual structural moiety, a bicyclic eudesmane-type sesquiterpene. As the biosynthesis of these rare terpene-nucleoside hybrid natural products remains elusive, we investigated secondary metabolomes and genomes of several 2-hydroxysorangiadenosine-producing myxobacteria. We report the isolation and full structure elucidation of 2-hydroxysorangiadenosine and its cytotoxic and antibiotic activities and propose a biosynthetic pathway in the myxobacterium Vitiosangium cumulatum MCy10943T.
  • New Peptaibiotics and a Cyclodepsipeptide from : Isolation, Identification, Cytotoxic and Nematicidal Activities.

    Moussa, Ashaimaa Y; Lambert, Christopher; Stradal, Theresia E B; Ashrafi, Samad; Maier, Wolfgang; Stadler, Marc; Helaly, Soleiman E; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (MDPI, 2020-03-22)
    Fungal associations with nematodes have attracted scientific attention because of the need to develop new biocontrol agents. In this context, Ijuhya vitellina, an antagonistic fungus previously isolated from the plant parasitic cyst nematode Heterodera filipjevi, was selected to carry out an in-depth metabolomic study for its active metabolites. Herein, three new nonapeptide peptaibols with leucinostatin based sequences were isolated and identified by 1, 2D NMR, and HR-ESI-MS-MS. The absolute configuration was assigned based on Marfay's analysis and Mosher ester formation. The new leucinostatins manifested moderate nematicidal effect against the plant pathogenic nematode Pratylenchus penetrans with LD90 values ranging from 5 to 7 µg/mL. Furthermore, a cyclodepsipeptide, named arthrichitin D, with five amino acid residues attached to a 3-hydroxy-2,4-dimethylhexadeca-4,6-dienoic fatty acid chain was discovered and showed weak nematicidal effect against Caenorhabditis elegans. Chaetoglobosin B and its 19-O-acetyl derivative were also obtained as minor metabolites, and the activity of chaetoglobosin B on the actin cytoskeleton of mammalian cells was assessed.

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