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  1. Article ; Online: A comparative analysis of remdesivir and other repurposed antivirals against SARS‐CoV‐2

    Alexander Simonis / Sebastian J Theobald / Gerd Fätkenheuer / Jan Rybniker / Jakob J Malin

    EMBO Molecular Medicine, Vol 13, Iss 1, Pp n/a-n/a (2021)

    2021  

    Abstract: Abstract The ongoing SARS‐CoV‐2 pandemic stresses the need for effective antiviral drugs that can quickly be applied in order to reduce morbidity, mortality, and ideally viral transmission. By repurposing of broadly active antiviral drugs and compounds ... ...

    Abstract Abstract The ongoing SARS‐CoV‐2 pandemic stresses the need for effective antiviral drugs that can quickly be applied in order to reduce morbidity, mortality, and ideally viral transmission. By repurposing of broadly active antiviral drugs and compounds that are known to inhibit viral replication of related viruses, several advances could be made in the development of treatment strategies against COVID‐19. The nucleoside analog remdesivir, which is known for its potent in vitro activity against Ebolavirus and other RNA viruses, was recently shown to reduce the time to recovery in patients with severe COVID‐19. It is to date the only approved antiviral for treating COVID‐19. Here, we provide a mechanism and evidence‐based comparative review of remdesivir and other repurposed drugs with proven in vitro activity against SARS‐CoV‐2.
    Keywords antivirals ; COVID‐19 ; remdesivir ; SARS‐CoV‐2 ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Comprehensive Host Cell-Based Screening Assays for Identification of Anti-Virulence Drugs Targeting Pseudomonas aeruginosa and Salmonella Typhimurium

    Julia von Ambüren / Fynn Schreiber / Julia Fischer / Sandra Winter / Edeltraud van Gumpel / Alexander Simonis / Jan Rybniker

    Microorganisms, Vol 8, Iss 1096, p

    2020  Volume 1096

    Abstract: The prevalence of bacterial pathogens being resistant to antibiotic treatment is increasing worldwide, leading to a severe global health challenge. Simultaneously, the development and approval of new antibiotics stagnated in the past decades, leading to ... ...

    Abstract The prevalence of bacterial pathogens being resistant to antibiotic treatment is increasing worldwide, leading to a severe global health challenge. Simultaneously, the development and approval of new antibiotics stagnated in the past decades, leading to an urgent need for novel approaches to avoid the spread of untreatable bacterial infections in the future. We developed a highly comprehensive screening platform based on quantification of pathogen driven host-cell death to detect new anti-virulence drugs targeting Pseudomonas aeruginosa ( Pa ) and Salmonella enterica serovar Typhimurium ( S T), both known for their emerging antibiotic resistance. By screening over 10,000 small molecules we could identify several substances showing promising effects on Pa and S T pathogenicity in our in vitro infection model. Importantly, we could detect compounds potently inhibiting bacteria induced killing of host cells and one novel comipound with impact on the function of the type 3 secretion system (T3SS) of S T. Thus, we provide proof of concept data of rapid and feasible medium- to high-throughput drug screening assays targeting virulence mechanisms of two major Gram-negative pathogens.
    Keywords multidrug-resistant pathogens ; host-directed therapies ; antibiotic drug screening ; Salmonella Typhimurium ; Pseudomonas aeruginosa ; type 3 secretion system ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS‐CoV‐2 mRNA vaccination

    Sebastian J Theobald / Alexander Simonis / Julie M Mudler / Ulrike Göbel / Richard Acton / Viktoria Kohlhas / Marie‐Christine Albert / Anna‐Maria Hellmann / Jakob J Malin / Sandra Winter / Michael Hallek / Henning Walczak / Phuong‐Hien Nguyen / Manuel Koch / Jan Rybniker

    EMBO Molecular Medicine, Vol 14, Iss 8, Pp n/a-n/a (2022)

    2022  

    Abstract: Abstract Durable cell‐mediated immune responses require efficient innate immune signaling and the release of pro‐inflammatory cytokines. How precisely mRNA vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains ... ...

    Abstract Abstract Durable cell‐mediated immune responses require efficient innate immune signaling and the release of pro‐inflammatory cytokines. How precisely mRNA vaccines trigger innate immune cells for shaping antigen specific adaptive immunity remains unknown. Here, we show that SARS‐CoV‐2 mRNA vaccination primes human monocyte‐derived macrophages for activation of the NLRP3 inflammasome. Spike protein exposed macrophages undergo NLRP3‐driven pyroptotic cell death and subsequently secrete mature interleukin‐1β. These effects depend on activation of spleen tyrosine kinase (SYK) coupled to C‐type lectin receptors. Using autologous cocultures, we show that SYK and NLRP3 orchestrate macrophage‐driven activation of effector memory T cells. Furthermore, vaccination‐induced macrophage priming can be enhanced with repetitive antigen exposure providing a rationale for prime‐boost concepts to augment innate immune signaling in SARS‐CoV‐2 vaccination. Collectively, these findings identify SYK as a regulatory node capable of differentiating between primed and unprimed macrophages, which modulate spike protein‐specific T cell responses.
    Keywords inflammasome ; innate immunity ; mRNA vaccines ; SARS‐CoV‐2 ; SYK signaling ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
    Subject code 570
    Language English
    Publishing date 2022-08-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Differential activation of acid sphingomyelinase and ceramide release determines invasiveness of Neisseria meningitidis into brain endothelial cells.

    Alexander Simonis / Sabrina Hebling / Erich Gulbins / Sibylle Schneider-Schaulies / Alexandra Schubert-Unkmeir

    PLoS Pathogens, Vol 10, Iss 6, p e

    2014  Volume 1004160

    Abstract: The interaction with brain endothelial cells is central to the pathogenicity of Neisseria meningitidis infections. Here, we show that N. meningitidis causes transient activation of acid sphingomyelinase (ASM) followed by ceramide release in brain ... ...

    Abstract The interaction with brain endothelial cells is central to the pathogenicity of Neisseria meningitidis infections. Here, we show that N. meningitidis causes transient activation of acid sphingomyelinase (ASM) followed by ceramide release in brain endothelial cells. In response to N. meningitidis infection, ASM and ceramide are displayed at the outer leaflet of the cell membrane and condense into large membrane platforms which also concentrate the ErbB2 receptor. The outer membrane protein Opc and phosphatidylcholine-specific phospholipase C that is activated upon binding of the pathogen to heparan sulfate proteoglycans, are required for N. meningitidis-mediated ASM activation. Pharmacologic or genetic ablation of ASM abrogated meningococcal internalization without affecting bacterial adherence. In accordance, the restricted invasiveness of a defined set of pathogenic isolates of the ST-11/ST-8 clonal complex into brain endothelial cells directly correlated with their restricted ability to induce ASM and ceramide release. In conclusion, ASM activation and ceramide release are essential for internalization of Opc-expressing meningococci into brain endothelial cells, and this segregates with invasiveness of N. meningitidis strains.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2014-06-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Long‐lived macrophage reprogramming drives spike protein‐mediated inflammasome activation in COVID‐19

    Sebastian J Theobald / Alexander Simonis / Theodoros Georgomanolis / Christoph Kreer / Matthias Zehner / Hannah S Eisfeld / Marie‐Christine Albert / Jason Chhen / Susanne Motameny / Florian Erger / Julia Fischer / Jakob J Malin / Jessica Gräb / Sandra Winter / Andromachi Pouikli / Friederike David / Boris Böll / Philipp Koehler / Kanika Vanshylla /
    Henning Gruell / Isabelle Suárez / Michael Hallek / Gerd Fätkenheuer / Norma Jung / Oliver A Cornely / Clara Lehmann / Peter Tessarz / Janine Altmüller / Peter Nürnberg / Hamid Kashkar / Florian Klein / Manuel Koch / Jan Rybniker

    EMBO Molecular Medicine, Vol 13, Iss 8, Pp n/a-n/a (2021)

    2021  

    Abstract: Abstract Innate immunity triggers responsible for viral control or hyperinflammation in COVID‐19 are largely unknown. Here we show that the SARS‐CoV‐2 spike protein (S‐protein) primes inflammasome formation and release of mature interleukin‐1β (IL‐1β) in ...

    Abstract Abstract Innate immunity triggers responsible for viral control or hyperinflammation in COVID‐19 are largely unknown. Here we show that the SARS‐CoV‐2 spike protein (S‐protein) primes inflammasome formation and release of mature interleukin‐1β (IL‐1β) in macrophages derived from COVID‐19 patients but not in macrophages from healthy SARS‐CoV‐2 naïve individuals. Furthermore, longitudinal analyses reveal robust S‐protein‐driven inflammasome activation in macrophages isolated from convalescent COVID‐19 patients, which correlates with distinct epigenetic and gene expression signatures suggesting innate immune memory after recovery from COVID‐19. Importantly, we show that S‐protein‐driven IL‐1β secretion from patient‐derived macrophages requires non‐specific monocyte pre‐activation in vivo to trigger NLRP3‐inflammasome signaling. Our findings reveal that SARS‐CoV‐2 infection causes profound and long‐lived reprogramming of macrophages resulting in augmented immunogenicity of the SARS‐CoV‐2 S‐protein, a major vaccine antigen and potent driver of adaptive and innate immune signaling.
    Keywords inflammasome ; innate immunity ; macrophage ; NLRP3 ; SARS‐CoV‐2 ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
    Subject code 616
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher Wiley
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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