Now showing items 1-20 of 3637

    • Immunotherapy with antibodies: Tumor development, immune defense and therapeutic antibodies

      Böldicke, Thomas; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (American Association for Cancer Research (AACR), 2021-01-01)
      Tumor development is based on mutations of genes involved in cell growth (e.g. transcription factors, growth receptors or intracellular signal molecules) or in suppressor genes (e.g. p53). During tumor growth cell clones are selected, which contain driver genes, leading to uncontrolled growth of these cell clones. During all phases of tumor development (immunosurveillance, equilibrium phase, escape of the tumor from the immune system) the interaction between the immune system and the tumor cells and the development of a chronic inflammation in the tumor microenvironment play a crucial role. The aim of cancer immunotherapy is to activate the immune system. A promising immunotherapy is based on antibodies that activate immune cells, inhibit tumor growth or lead to destruction of tumor cells. Applied are recombinant IgG antibodies or genetically engineered antibody fragments against tumor-associated antigens (TAA’s). They are applied singularly or in combination with chemo- or radiotherapy. Promising are checkpoint antibodies, which abrogate blocking of cytotoxic CD8+ T cells and CD4+ T cells by tumor cells and/or dendritic cells. Other successfully applied antibodies are bispecific antibodies (recognize T‑cell and tumor cell), chimeric antigen receptors (CARs) for T cell therapy, immunocytokines (cytokines fused to antibodies) and immunotoxins (toxins fused to antibodies). In addition intracellular antibodies successfully tested in xenograft tumor mouse models have promising therapeutic potential.
    • Regulatory T Cells in an Endogenous Mouse Lymphoma Recognize Specific Antigen Peptides and Contribute to Immune Escape.

      Ahmetlić, Fatima; Riedel, Tanja; Hömberg, Nadine; Bauer, Vera; Trautwein, Nico; Geishauser, Albert; Sparwasser, Tim; Stevanović, Stefan; Röcken, Martin; Mocikat, Ralph; et al. (American Association for Cancer Research (AACR), 2019-03-20)
      Foxp3+ regulatory T cells (Tregs) sustain immune homeostasis and may contribute to immune escape in malignant disease. As a prerequisite for developing immunologic approaches in cancer therapy, it is necessary to understand the ontogeny and the antigenic specificities of tumor-infiltrating Tregs. We addressed this question by using a λ-MYC transgenic mouse model of endogenously arising B-cell lymphoma, which mirrors key features of human Burkitt lymphoma. We show that Foxp3+ Tregs suppress antitumor responses in endogenous lymphoma. Ablation of Foxp3+ Tregs significantly delayed tumor development. The ratio of Treg to effector T cells was elevated in growing tumors, which could be ascribed to differential proliferation. The Tregs detected were mainly natural Tregs that apparently recognized self-antigens. We identified MHC class II-restricted nonmutated self-epitopes, which were more prevalent in lymphoma than in normal B cells and could be recognized by Tregs. These epitopes were derived from proteins that are associated with cellular processes related to malignancy and may be overexpressed in the tumor.
    • How Insertion of a Single Tryptophan in the N-Terminus of a Cecropin A-Melittin Hybrid Peptide Changes Its Antimicrobial and Biophysical Profile.

      Ferreira, Ana Rita; Teixeira, Cátia; Sousa, Carla F; Bessa, Lucinda J; Gomes, Paula; Gameiro, Paula; HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany. (MDPI, 2021-01-12)
      n the era of antibiotic resistance, there is an urgent need for efficient antibiotic therapies to fight bacterial infections. Cationic antimicrobial peptides (CAMP) are promising lead compounds given their membrane-targeted mechanism of action, and high affinity towards the anionic composition of bacterial membranes. We present a new CAMP, W-BP100, derived from the highly active BP100, holding an additional tryptophan at the N-terminus. W-BP100 showed a broader antibacterial activity, demonstrating a potent activity against Gram-positive strains. Revealing a high partition constant towards anionic over zwitterionic large unilamellar vesicles and inducing membrane saturation at a high peptide/lipid ratio, W-BP100 has a preferential location for hydrophobic environments. Contrary to BP100, almost no aggregation of anionic vesicles is observed around saturation conditions and at higher concentrations no aggregation is observed. With these results, it is possible to state that with the incorporation of a single tryptophan to the N-terminus, a highly active peptide was obtained due to the π-electron system of tryptophan, resulting in negatively charged clouds, that participate in cation-π interactions with lysine residues. Furthermore, we propose that W-BP100 action can be achieved by electrostatic interactions followed by peptide translocation.
    • Cell sheet technology: Influence of culture conditions on in vitro-cultivated corneal stromal tissue for regenerative therapies of the ocular surface.

      Hasenzahl, Meike; Müsken, Mathias; Mertsch, Sonja; Schrader, Stefan; Reichl, Stephan; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Wiley, 2021-02-03)
      The in vitro reconstruction of stromal tissue by long-term cultivation of corneal fibroblasts is a smart approach for regenerative therapies of ocular surface diseases. However, systematic investigations evaluating optimized cultivation protocols for the realization of a biomaterial are lacking. This study investigated the influence of supplements to the culture media of human corneal fibroblasts on the formation of a cell sheet consisting of cells and extracellular matrix. Among the supplements studied are vitamin C, fetal bovine serum, L-glutamine, components of collagen such as L-proline, L-4-hydroxyproline and glycine, and TGF-β1, bFGF, IGF-2, PDGF-BB and insulin. After long-term cultivation, the proliferation, collagen and glycosaminoglycan content and light transmission of the cell sheets were examined. Biomechanical properties were investigated by tensile tests and the ultrastructure was characterized by electron microscopy, small-angle X-ray scattering, antibody staining and ELISA. The synthesis of extracellular matrix was significantly increased by cultivation with insulin or TGF-β1, each with vitamin C. The sheets exhibited a high transparency and suitable material properties. The production of a transparent, scaffold-free, potentially autologous, in vitro-generated construct by culturing fibroblasts with extracellular matrix synthesis-stimulating supplements represents a promising approach for a biomaterial that can be used for ocular surface reconstruction in slowly progressing diseases.
    • Pulmonary Surfactant and Drug Delivery: An Interface-Assisted Carrier to Deliver Surfactant Protein SP-D Into the Airways.

      García-Mouton, Cristina; Hidalgo, Alberto; Arroyo, Raquel; Echaide, Mercedes; Cruz, Antonio; Pérez-Gil, Jesús; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Frontiers, 2021-01-18)
      This work is focused on the potential use of pulmonary surfactant to deliver full-length recombinant human surfactant protein SP-D (rhSP-D) using the respiratory air-liquid interface as a shuttle. Surfactant protein D (SP-D) is a collectin protein present in the pulmonary surfactant (PS) system, involved in innate immune defense and surfactant homeostasis. It has been recently suggested as a potential therapeutic to alleviate inflammatory responses and lung diseases in preterm infants suffering from respiratory distress syndrome (RDS) or bronchopulmonary dysplasia (BPD). However, none of the current clinical surfactants used for surfactant replacement therapy (SRT) to treat RDS contain SP-D. The interaction of SP-D with surfactant components, the potential of PS as a respiratory drug delivery system and the possibility to produce recombinant versions of human SP-D, brings the possibility of delivering clinical surfactants supplemented with SP-D. Here, we used an in vitro setup that somehow emulates the respiratory air-liquid interface to explore this novel approach. It consists in two different compartments connected with a hydrated paper bridge forming a continuous interface. We firstly analyzed the adsorption and spreading of rhSP-D alone from one compartment to another over the air-liquid interface, observing low interfacial activity. Then, we studied the interfacial spreading of the protein co-administered with PS, both at different time periods or as a mixed formulation, and which oligomeric forms of rhSP-D better traveled associated with PS. The results presented here demonstrated that PS may transport rhSP-D long distances over air-liquid interfaces, either as a mixed formulation or separately in a close window time, opening the doors to empower the current clinical surfactants and SRT.
    • Broad Spectrum Antibiotic Xanthocillin X Effectively Kills Acinetobacter baumannii via Dysregulation of Heme Biosynthesis

      Hübner, Ines; Shapiro, Justin A.; Hoßmann, Jörn; Drechsel, Jonas; Hacker, Stephan M.; Rather, Philip N.; Pieper, Dietmar H.; Wuest, William M.; Sieber, Stephan A.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (American Chemical Society (ACS), 2021-01-20)
      Isonitrile natural products exhibit promising antibacterial activities. However, their mechanism of action (MoA) remains largely unknown. Based on the nanomolar potency of xanthocillin X (Xan) against diverse difficult-to-treat Gram-negative bacteria, including the critical priority pathogen Acinetobacter baumannii, we performed in-depth studies to decipher its MoA. While neither metal binding nor cellular protein targets were detected as relevant for Xan’s antibiotic effects, sequencing of resistant strains revealed a conserved mutation in the heme biosynthesis enzyme porphobilinogen synthase (PbgS). This mutation caused impaired enzymatic efficiency indicative of reduced heme production. This discovery led to the validation of an untapped mechanism, by which direct heme sequestration of Xan prevents its binding into cognate enzyme pockets resulting in uncontrolled cofactor biosynthesis, accumulation of porphyrins, and corresponding stress with deleterious effects for bacterial viability. Thus, Xan represents a promising antibiotic displaying activity even against multidrug resistant strains, while exhibiting low toxicity to human cells.
    • Cyclic Di-Adenosine Monophosphate: A Promising Adjuvant Candidate for the Development of Neonatal Vaccines.

      Lirussi, Darío; Weissmann, Sebastian Felix; Ebensen, Thomas; Nitsche-Gloy, Ursula; Franz, Heiko B G; Guzmán, Carlos A; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (MDPI, 2021-02-01)
      Underdeveloped immunity during the neonatal age makes this period one of the most dangerous during the human lifespan, with infection-related mortality being one of the highest of all age groups. It is also discussed that vaccination during this time window may result in tolerance rather than in productive immunity, thus raising concerns about the overall vaccine-mediated protective efficacy. Cyclic di-nucleotides (CDN) are bacterial second messengers that are rapidly sensed by the immune system as a danger signal, allowing the utilization of these molecules as potent activators of the immune response. We have previously shown that cyclic di-adenosine monophosphate (CDA) is a potent and versatile adjuvant capable of promoting humoral and cellular immunity. We characterize here the cytokine profiles elicited by CDA in neonatal cord blood in comparison with other promising neonatal adjuvants, such as the imidazoquinoline resiquimod (R848), which is a synthetic dual TLR7 and TLR8 agonist. We observed superior activity of CDA in eliciting T helper 1 (Th1) and T follicular helper (TfH) cytokines in cells from human cord blood when compared to R848. Additional in vivo studies in mice showed that neonatal priming in a three-dose vaccination schedule is beneficial when CDA is used as a vaccine adjuvant. Humoral antibody titers were significantly higher in mice that received a neonatal prime as compared to those that did not. This effect was absent when using other adjuvants that were reported as suitable for neonatal vaccination. The biological significance of this immune response was assessed by a challenge with a genetically modified influenza H1N1 PR8 virus. The obtained results confirmed that CDA performed better than any other adjuvant tested. Altogether, our results suggest that CDA is a potent adjuvant in vitro on human cord blood, and in vivo in newborn mice, and thus a suitable candidate for the development of neonatal vaccines. Keywords: cyclic di-adenosine monophosphate (CDA); cyclic di-nucleotides (CDN); first dose efficacy; neonatal vaccines; stimulator of interferon genes (STING).
    • Enhancing glycan stabilityviasite-selective fluorination: modulating substrate orientation by molecular design

      Axer, Alexander; Jumde, Ravindra P.; Adam, Sebastian; Faust, Andreas; Schäfers, Michael; Fobker, Manfred; Koehnke, Jesko; Hirsch, Anna K.H.; Gilmour, Ryan; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Royal Chemistry Society (RCS), 2021-01-28)
      ingle site OH → F substitution at the termini of maltotetraose leads to significantly improved hydrolytic stability towards α-amylase and α-glucosidase relative to the natural compound. To explore the effect of molecular editing, selectively modified oligosaccharides were preparedviaa convergent α-selective strategy. Incubation experiments in purified α-amylase and α-glucosidase, and in human and murine blood serum, provide insight into the influence of fluorine on the hydrolytic stability of these clinically important scaffolds. Enhancements ofca. 1 order of magnitude result from these subtle single point mutations. Modification at the monosaccharide furthest from the probable enzymatic cleavage termini leads to the greatest improvement in stability. In the case of α-amylase, docking studies revealed that retentive C2-fluorination at the reducing end inverts the orientation in which the substrate is bound. A co-crystal structure of human α-amylase revealed maltose units bound at the active-site. In view of the evolving popularity of C(sp3)-F bioisosteres in medicinal chemistry, and the importance of maltodextrins in bacterial imaging, this discovery begins to reconcile the information-rich nature of carbohydrates with their intrinsic hydrolytic vulnerabilities. © The Royal Society of Chemistry 2020.
    • Misinterpretation of the odds ratios.

      Fernández, Nathalie; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Elsevier, 2020-05-11)
      No abstract available
    • A Grad-seq View of RNA and Protein Complexes in Pseudomonas aeruginosa under Standard and Bacteriophage Predation Conditions.

      Gerovac, Milan; Wicke, Laura; Chihara, Kotaro; Schneider, Cornelius; Lavigne, Rob; Vogel, Jörg; HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany. (American Society for Microbiology (ASM), 2021-02-09)
      The Gram-negative rod-shaped bacterium Pseudomonas aeruginosa is not only a major cause of nosocomial infections but also serves as a model species of bacterial RNA biology. While its transcriptome architecture and posttranscriptional regulation through the RNA-binding proteins Hfq, RsmA, and RsmN have been studied in detail, global information about stable RNA-protein complexes in this human pathogen is currently lacking. Here, we implement gradient profiling by sequencing (Grad-seq) in exponentially growing P. aeruginosa cells to comprehensively predict RNA and protein complexes, based on glycerol gradient sedimentation profiles of >73% of all transcripts and ∼40% of all proteins. As to benchmarking, our global profiles readily reported complexes of stable RNAs of P. aeruginosa, including 6S RNA with RNA polymerase and associated product RNAs (pRNAs). We observe specific clusters of noncoding RNAs, which correlate with Hfq and RsmA/N, and provide a first hint that P. aeruginosa expresses a ProQ-like FinO domain-containing RNA-binding protein. To understand how biological stress may perturb cellular RNA/protein complexes, we performed Grad-seq after infection by the bacteriophage ΦKZ. This model phage, which has a well-defined transcription profile during host takeover, displayed efficient translational utilization of phage mRNAs and tRNAs, as evident from their increased cosedimentation with ribosomal subunits. Additionally, Grad-seq experimentally determines previously overlooked phage-encoded noncoding RNAs. Taken together, the Pseudomonas protein and RNA complex data provided here will pave the way to a better understanding of RNA-protein interactions during viral predation of the bacterial cell.IMPORTANCE Stable complexes by cellular proteins and RNA molecules lie at the heart of gene regulation and physiology in any bacterium of interest. It is therefore crucial to globally determine these complexes in order to identify and characterize new molecular players and regulation mechanisms. Pseudomonads harbor some of the largest genomes known in bacteria, encoding ∼5,500 different proteins. Here, we provide a first glimpse on which proteins and cellular transcripts form stable complexes in the human pathogen Pseudomonas aeruginosa We additionally performed this analysis with bacteria subjected to the important and frequently encountered biological stress of a bacteriophage infection. We identified several molecules with established roles in a variety of cellular pathways, which were affected by the phage and can now be explored for their role during phage infection. Most importantly, we observed strong colocalization of phage transcripts and host ribosomes, indicating the existence of specialized translation mechanisms during phage infection. All data are publicly available in an interactive and easy to use browser.
    • COVID-19 immune signatures reveal stable antiviral T cell function despite declining humoral responses.

      Bonifacius, Agnes; Tischer-Zimmermann, Sabine; Dragon, Anna C; Gussarow, Daniel; Vogel, Alexander; Krettek, Ulrike; Gödecke, Nina; Yilmaz, Mustafa; Kraft, Anke R M; Hoeper, Marius M; et al.
      Cellular and humoral immunity to SARS-CoV-2 is critical to control primary infection and correlates with severity of disease. The role of SARS-CoV-2-specific T cell immunity, its relationship to antibodies, and pre-existing immunity against endemic coronaviruses (huCoV), which has been hypothesized to be protective, were investigated in 82 healthy donors (HDs), 204 recovered (RCs), and 92 active COVID-19 patients (ACs). ACs had high amounts of anti-SARS-CoV-2 nucleocapsid and spike IgG but lymphopenia and overall reduced antiviral T cell responses due to the inflammatory milieu, expression of inhibitory molecules (PD-1, Tim-3) as well as effector caspase-3, -7, and -8 activity in T cells. SARS-CoV-2-specific T cell immunity conferred by polyfunctional, mainly interferon-γ-secreting CD4+ T cells remained stable throughout convalescence, whereas humoral responses declined. Immune responses toward huCoV in RCs with mild disease and strong cellular SARS-CoV-2 T cell reactivity imply a protective role of pre-existing immunity against huCoV.
    • Three new species of Hypoxylon and new records of Xylariales from Panama

      Cedeño–Sanchez, M; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Mushroom Research Foundation, 2020-03-31)
      This is a continuation of the papers “Towards a classification of Sordariomycetes” (2015) and “Families of Sordariomycetes” (2016) in which we compile a treatment of the class Sordariomycetes. The present treatment is needed as our knowledge has rapidly increased, from 32 orders, 105 families and 1331 genera in 2016, to 45 orders, 167 families and 1499 genera (with 308 genera incertae sedis) at the time of publication. In this treatment we provide notes on each order, families and short notes on each genus. We provide up-to-date DNA based phylogenies for 45 orders and 163 families. Three new genera and 16 new species are introduced with illustrations and descriptions, while 23 new records and three new species combinations are provided. We also list 308 taxa in Sordariomycetes genera incertae sedis. For each family we provide general descriptions and illustrate the type genus or another genus, the latter where the placement has generally been confirmed with molecular data. Both the sexual and asexual morphs representative of a family are illustrated where available. Notes on ecological and economic considerations are also given
    • Refined families of Sordariomycetes

      Hyde, KD; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Mushroom Research Foundation, 2020-03-31)
      This is a continuation of the papers “Towards a classification of Sordariomycetes” (2015) and “Families of Sordariomycetes” (2016) in which we compile a treatment of the class Sordariomycetes. The present treatment is needed as our knowledge has rapidly increased, from 32 orders, 105 families and 1331 genera in 2016, to 45 orders, 167 families and 1499 genera (with 308 genera incertae sedis) at the time of publication. In this treatment we provide notes on each order, families and short notes on each genus. We provide up-to-date DNA based phylogenies for 45 orders and 163 families. Three new genera and 16 new species are introduced with illustrations and descriptions, while 23 new records and three new species combinations are provided. We also list 308 taxa in Sordariomycetes genera incertae sedis. For each family we provide general descriptions and illustrate the type genus or another genus, the latter where the placement has generally been confirmed with molecular data. Both the sexual and asexual morphs representative of a family are illustrated where available. Notes on ecological and economic considerations are also given.
    • Second-generation lung-on-a-chip with an array of stretchable alveoli made with a biological membrane.

      Zamprogno, Pauline; Wüthrich, Simon; Achenbach, Sven; Thoma, Giuditta; Stucki, Janick D; Hobi, Nina; Schneider-Daum, Nicole; Lehr, Claus-Michael; Huwer, Hanno; Geiser, Thomas; et al. (Nature Pulishing Group, 2021-02-05)
      The air-blood barrier with its complex architecture and dynamic environment is difficult to mimic in vitro. Lung-on-a-chips enable mimicking the breathing movements using a thin, stretchable PDMS membrane. However, they fail to reproduce the characteristic alveoli network as well as the biochemical and physical properties of the alveolar basal membrane. Here, we present a lung-on-a-chip, based on a biological, stretchable and biodegradable membrane made of collagen and elastin, that emulates an array of tiny alveoli with in vivo-like dimensions. This membrane outperforms PDMS in many ways: it does not absorb rhodamine-B, is biodegradable, is created by a simple method, and can easily be tuned to modify its thickness, composition and stiffness. The air-blood barrier is reconstituted using primary lung alveolar epithelial cells from patients and primary lung endothelial cells. Typical alveolar epithelial cell markers are expressed, while the barrier properties are preserved for up to 3 weeks.
    • No impact of a short-term climatic "El Niño" fluctuation on gut microbial diversity in populations of the Galápagos marine iguana (Amblyrhynchus cristatus).

      Ibáñez, Alejandro; Bletz, Molly C; Quezada, Galo; Geffers, Robert; Jarek, Michael; Vences, Miguel; Steinfartz, Sebastian; HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany. (Springer, 2021-02-02)
      Gut microorganisms are crucial for many biological functions playing a pivotal role in the host's well-being. We studied gut bacterial community structure of marine iguana populations across the Galápagos archipelago. Marine iguanas depend heavily on their specialized gut microbiome for the digestion of dietary algae, a resource whose growth was strongly reduced by severe "El Niño"-related climatic fluctuations in 2015/2016. As a consequence, marine iguana populations showed signs of starvation as expressed by a poor body condition. Body condition indices (BCI) varied between island populations indicating that food resources (i.e., algae) are affected differently across the archipelago during 'El Niño' events. Though this event impacted food availability for marine iguanas, we found that reductions in body condition due to "El Niño"-related starvation did not result in differences in bacterial gut community structure. Species richness of gut microorganisms was instead correlated with levels of neutral genetic diversity in the distinct host populations. Our data suggest that marine iguana populations with a higher level of gene diversity and allelic richness may harbor a more diverse gut microbiome than those populations with lower genetic diversity. Since low values of these diversity parameters usually correlate with small census and effective population sizes, we use our results to propose a novel hypothesis according to which small and genetically less diverse host populations might be characterized by less diverse microbiomes. Whether such genetically depauperate populations may experience additional threats from reduced dietary flexibility due to a limited intestinal microbiome is currently unclear and calls for further investigation.
    • Transcriptome profiling and protease inhibition experiments identify proteases that activate H3N2 influenza A and influenza B viruses in murine airways.

      Harbig, Anne; Mernberger, Marco; Bittel, Linda; Pleschka, Stephan; Schughart, Klaus; Steinmetzer, Torsten; Stiewe, Thorsten; Nist, Andrea; Böttcher-Friebertshäuser, Eva; HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany. (Elsevier, 2020-04-17)
      Cleavage of influenza virus hemagglutinin (HA) by host proteases is essential for virus infectivity. HA of most influenza A and B (IAV/IBV) viruses is cleaved at a monobasic motif by trypsin-like proteases. Previous studies have reported that transmembrane serine protease 2 (TMPRSS2) is essential for activation of H7N9 and H1N1pdm IAV in mice but that H3N2 IAV and IBV activation is independent of TMPRSS2 and carried out by as-yet-undetermined protease(s). Here, to identify additional H3 IAV- and IBV-activating proteases, we used RNA-Seq to investigate the protease repertoire of murine lower airway tissues, primary type II alveolar epithelial cells (AECIIs), and the mouse lung cell line MLE-15. Among 13 candidates identified, TMPRSS4, TMPRSS13, hepsin, and prostasin activated H3 and IBV HA in vitro IBV activation and replication was reduced in AECIIs from Tmprss2/Tmprss4-deficient mice compared with WT or Tmprss2-deficient mice, indicating that murine TMPRSS4 is involved in IBV activation. Multicycle replication of H3N2 IAV and IBV in AECIIs of Tmprss2/Tmprss4-deficient mice varied in sensitivity to protease inhibitors, indicating that different, but overlapping, sets of murine proteases facilitate H3 and IBV HA cleavages. Interestingly, human hepsin and prostasin orthologs did not activate H3, but they did activate IBV HA in vitro Our results indicate that TMPRSS4 is an IBV-activating protease in murine AECIIs and suggest that TMPRSS13, hepsin, and prostasin cleave H3 and IBV HA in mice. They further show that hepsin and prostasin orthologs might contribute to the differences observed in TMPRSS2-independent activation of H3 in murine and human airways.
    • One stop shop IV: taxonomic update with molecular phylogeny for important phytopathogenic genera: 76–100 (2020)

      Jayawardena, Ruvishika S.; Hyde, Kevin D.; Chen, Yi Jyun; Papp, Viktor; Palla, Balázs; Papp, Dávid; Bhunjun, Chitrabhanu S.; Hurdeal, Vedprakash G.; Senwanna, Chanokned; Manawasinghe, Ishara S.; et al. (Springer Science and Business Media LLC, 2020-09-24)
      This is a continuation of a series focused on providing a stable platform for the taxonomy of phytopathogenic fungi and fungus-like organisms. This paper focuses on one family: Erysiphaceae and 24 phytopathogenic genera: Armillaria, Barriopsis, Cercospora, Cladosporium, Clinoconidium, Colletotrichum, Cylindrocladiella, Dothidotthia,, Fomitopsis, Ganoderma, Golovinomyces, Heterobasidium, Meliola, Mucor, Neoerysiphe, Nothophoma, Phellinus, Phytophthora, Pseudoseptoria, Pythium, Rhizopus, Stemphylium, Thyrostroma and Wojnowiciella. Each genus is provided with a taxonomic background, distribution, hosts, disease symptoms, and updated backbone trees. Species confirmed with pathogenicity studies are denoted when data are available. Six of the genera are updated from previous entries as many new species have been described.
    • Modulating the Barrier Function of Human Alveolar Epithelial (hAELVi) Cell Monolayers as a Model of Inflammation.

      Metz, Julia Katharina; Wiegand, Birgit; Schnur, Sabrina; Knoth, Katharina; Schneider-Daum, Nicole; Groß, Henrik; Croston, Glenn; Reinheimer, Torsten Michael; Lehr, Claus-Michael; Hittinger, Marius; et al. (SAGE Publications, 2021-01-29)
      The incidence of inflammatory lung diseases such as acute respiratory distress syndrome (ARDS) remains an important problem, particularly in the present time with the Covid-19 pandemic. However, an adequate in vitro test system to monitor the barrier function of the alveolar epithelium during inflammation and for assessing anti-inflammatory drugs is urgently needed. Therefore, we treated human Alveolar Epithelial Lentivirus-immortalised cells (hAELVi cells) with the pro-inflammatory cytokines TNF-α (25 ng/ml) and IFN-γ (30 ng/ml), in the presence or absence of hydrocortisone (HC). While TNF-α and IFN-γ are known to reduce epithelial barrier properties, HC could be expected to protect the barrier function and result in an anti-inflammatory effect. We investigated the impact of anti-inflammatory/inflammatory treatment on transepithelial electrical resistance (TEER) and the apparent permeability coefficient (P app ) of the low permeability marker sodium fluorescein (NaFlu). After incubating hAELVi cells for 48 hours with a combination of TNF-α and IFN-γ, there was a significant decrease in TEER and a significant increase in the P app . The presence of HC maintained the TEER values and barrier properties, so that no significant P app change was observed. By using hAELVi cells to study anti-inflammatory drugs in vitro, the need for animal experiments could be reduced and pulmonary drug development accelerated.
    • Fungi on wild seeds and fruits

      Perera, R. H.; Hyde, K. D.; Maharachchikumbura, S. S.N.; Jones, E. B.G.; McKenzie, E. H.C.; Stadler, M.; Lee, H. B.; Samarakoon, M. C.; Ekanayaka, A. H.; Camporesi, E.; et al. (Mycosphere Press, 2020-09-17)
      This paper reviews and determines the fungi growing on seeds and fruits of wild plants in various habitats. Such fungi colonise a wide range of substrates with most reported from cones, cupules, and leguminous pods that are high in cellulose and lignin content. There are 1348 fungal species (belonging to 230 families and 609 genera) reported from wild seeds and fruits in 84 countries, listed in this paper. Of these, 300 fungi were described from wild seeds and fruit substrates. Members of the Fabaceae support the highest number of taxa, namely 19% of the novel wild fruit fungi. Twenty-eight genera, including 5 fossil fungal genera have been described from wild seeds and fruits: Agarwalomyces, Amorocoelophoma, Anisogenispora, Archephoma, Centrolepidosporium, Cylindroaseptospora, Cylindromyces, Davidhawksworthia, Delonicicola, Discotubeufia, Glaxoa, Kionocephala, Leucaenicola, Naranus, Neolindgomyces, Pleohelicoon, Quercicola, Remotididymella, Repetoblastiella, Restilago, Soloacrosporiella, Strobiloscypha and Tainosphaeria. Archephoma, Meniscoideisporites, Palaeodiplodites, Palaeopericonia and Xylohyphites are the new fossil fungal genera. Fungal asexual morphs predominate on wild seeds and fruits rather than the sexual morphs. The dominant fungal genera on wild seeds and fruits include Alternaria, Aspergillus, Candida, Chaetomium, Cladosporium, Colletotrichum, Curvularia, Diaporthe, Drechslera, Fusarium, Mucor, Penicillium, Pestalotiopsis, Restiosporium, Rhizopus, Talaromyces, Trichoderma and Xylaria. Certain assemblages of fungi have specific and distinct relationships with their hosts, especially Xylaria species (e.g., Xylaria magnoliae on Magnolia fruits; X. xanthinovelutina (= X. ianthino-velutina) on Fabaceae pods; X. carpophila on Fagus cupules; X. persicaria on liquidambar fruits). Whether these species occur as endophytes and become saprobes following fruit fall requires further investigation. In this study, we also made several sexual morph collections of sordariomycetous taxa from different seed and fruit substrates mainly from Thailand, with a few from the UK. These include 15 new species, 13 new host records and 1 new geographical record. The new species are described and illustrated. © 2020, Guizhou Key Laboratory of Agricultural Biotechnology
    • Efficient IL-2R signaling differentially affects the stability, function, and composition of the regulatory T-cell pool.

      Permanyer, Marc; Bošnjak, Berislav; Glage, Silke; Friedrichsen, Michaela; Floess, Stefan; Huehn, Jochen; Patzer, Gwendolyn E; Odak, Ivan; Eckert, Nadine; Zargari, Razieh; et al. (Springer Nature, 2021-01-06)
      Signaling via interleukin-2 receptor (IL-2R) is a requisite for regulatory T (Treg) cell identity and function. However, it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis, lineage stability and function in both resting and inflammatory conditions. Here, we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25, the α-chain of IL-2R, which resulted in diminished receptor expression and reduced IL-2R signaling. Under noninflammatory conditions, Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease. In contrast, Cd25Y129H Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model, indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments. Moreover, single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets. Thus, partial loss of IL-2R signaling differentially interferes with the maintenance, heterogeneity, and suppressive function of the Treg cell pool.