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Article ; Online: The role of acid sphingomyelinase and modulation of sphingolipid metabolism in bacterial infection.

Simonis, Alexander / Schubert-Unkmeir, Alexandra

2018 Volume 399, Issue 10, Page(s) 1135–1146

Abstract: Acid sphingomyelinase (ASM) is a key enzyme in sphingolipid metabolism that converts sphingomyelin to ceramide, thereby modulating membrane structures and signal transduction. Bacterial pathogens can manipulate ASM activity and function, and use host ... ...

Abstract	Acid sphingomyelinase (ASM) is a key enzyme in sphingolipid metabolism that converts sphingomyelin to ceramide, thereby modulating membrane structures and signal transduction. Bacterial pathogens can manipulate ASM activity and function, and use host sphingolipids during multiple steps of their infection process. An increase in ceramides upon infection results in the formation of ceramide-enriched membrane platforms that serve to cluster receptor molecules and organize intracellular signaling molecules, thus facilitating bacterial uptake. In this review, we focus on how extracellular bacterial pathogens target ASM and modulate membrane properties and signaling pathways to gain entry into eukaryotic cells or induce cell death. We describe how intracellular pathogens interfere with the intralysosomal functions of ASM to favor replication and survival. In addition, bacteria utilize their own sphingomyelinases as virulence factors to modulate sphingolipid metabolism. The potential of ASM as a target for treating bacterial infections is also discussed.
MeSH term(s)	Animals ; Bacterial Infections/enzymology ; Bacterial Infections/metabolism ; Humans ; Sphingolipids/metabolism ; Sphingomyelin Phosphodiesterase/metabolism
Chemical Substances	Sphingolipids ; Sphingomyelin Phosphodiesterase (EC 3.1.4.12)
Language	English
Publishing date	2018-06-20
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1334659-3
ISSN	1437-4315 ; 1431-6730 ; 1432-0355
ISSN (online)	1437-4315
ISSN	1431-6730 ; 1432-0355
DOI	10.1515/hsz-2018-0200
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Article ; Online: Interactions of meningococcal virulence factors with endothelial cells at the human blood-cerebrospinal fluid barrier and their role in pathogenicity.

Simonis, Alexander / Schubert-Unkmeir, Alexandra

FEBS letters

2016 Volume 590, Issue 21, Page(s) 3854–3867

Abstract: The Gram-negative extracellular bacterium Neisseria meningitidis is one of the most common aetiological agents of bacterial meningitis affecting predominantly young children worldwide. This bacterium is normally a quiescent coloniser of the upper ... ...

Abstract	The Gram-negative extracellular bacterium Neisseria meningitidis is one of the most common aetiological agents of bacterial meningitis affecting predominantly young children worldwide. This bacterium is normally a quiescent coloniser of the upper respiratory tract, but in some individuals it enters the blood stream and causes invasive diseases, such as septicaemia and meningitis. Interactions of N. meningitidis with human endothelial cells are crucially involved in pathogencitiy, and great efforts have been made to understand these molecular interactions. The aim of this review article is to provide an overview of the interactions of meningococcal virulence factors with host endothelial cells at the blood-cerebrospinal fluid barrier.
MeSH term(s)	Blood-Brain Barrier/microbiology ; Cerebrospinal Fluid/microbiology ; Endothelial Cells/microbiology ; Humans ; Meningococcal Infections/microbiology ; Neisseria meningitidis/metabolism ; Neisseria meningitidis/pathogenicity ; Respiratory System/microbiology ; Virulence Factors/metabolism
Chemical Substances	Virulence Factors
Language	English
Publishing date	2016-11
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.12344
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Article ; Online: A comparative analysis of remdesivir and other repurposed antivirals against SARS-CoV-2.

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

EMBO molecular medicine

2020 Volume 13, Issue 1, Page(s) e13105

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 ... ...

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.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/pharmacology ; Adenosine Monophosphate/therapeutic use ; Alanine/analogs & derivatives ; Alanine/pharmacology ; Alanine/therapeutic use ; Amides/pharmacology ; Amides/therapeutic use ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Benzamidines ; Drug Repositioning/methods ; Esters/pharmacology ; Esters/therapeutic use ; Guanidines/pharmacology ; Guanidines/therapeutic use ; Guanine/pharmacology ; Guanine/therapeutic use ; Humans ; Indoles/pharmacology ; Indoles/therapeutic use ; Lopinavir/pharmacology ; Lopinavir/therapeutic use ; Protease Inhibitors/pharmacology ; Protease Inhibitors/therapeutic use ; Pyrazines/pharmacology ; Pyrazines/therapeutic use ; Ribavirin/pharmacology ; Ribavirin/therapeutic use ; Ritonavir/pharmacology ; Ritonavir/therapeutic use ; SARS-CoV-2/drug effects ; SARS-CoV-2/physiology ; Virus Internalization/drug effects ; Virus Replication/drug effects ; COVID-19 Drug Treatment
Chemical Substances	Amides ; Antiviral Agents ; Benzamidines ; Esters ; Guanidines ; Indoles ; Protease Inhibitors ; Pyrazines ; camostat (0FD207WKDU) ; Lopinavir (2494G1JF75) ; penciclovir (359HUE8FJC) ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Ribavirin (49717AWG6K) ; Guanine (5Z93L87A1R) ; umifenovir (93M09WW4RU) ; favipiravir (EW5GL2X7E0) ; Ritonavir (O3J8G9O825) ; Alanine (OF5P57N2ZX) ; nafamostat (Y25LQ0H97D)
Keywords	covid19
Language	English
Publishing date	2020-11-03
Publishing country	England
Document type	Comparative Study ; Journal Article ; Review
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.202013105
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Article ; Online: Viral Glycoproteins Induce NLRP3 Inflammasome Activation and Pyroptosis in Macrophages.

Eisfeld, Hannah S / Simonis, Alexander / Winter, Sandra / Chhen, Jason / Ströh, Luisa J / Krey, Thomas / Koch, Manuel / Theobald, Sebastian J / Rybniker, Jan

Viruses

2021 Volume 13, Issue 10

Abstract: Infections with viral pathogens are widespread and can cause a variety of different diseases. In-depth knowledge about viral triggers initiating an immune response is necessary to decipher viral pathogenesis. Inflammasomes, as part of the innate immune ... ...

Abstract	Infections with viral pathogens are widespread and can cause a variety of different diseases. In-depth knowledge about viral triggers initiating an immune response is necessary to decipher viral pathogenesis. Inflammasomes, as part of the innate immune system, can be activated by viral pathogens. However, viral structural components responsible for inflammasome activation remain largely unknown. Here we analyzed glycoproteins derived from SARS-CoV-1/2, HCMV and HCV, required for viral entry and fusion, as potential triggers of NLRP3 inflammasome activation and pyroptosis in THP-1 macrophages. All tested glycoproteins were able to potently induce NLRP3 inflammasome activation, indicated by ASC-SPECK formation and secretion of cleaved IL-1β. Lytic cell death via gasdermin D (GSDMD), pore formation, and pyroptosis are required for IL-1β release. As a hallmark of pyroptosis, we were able to detect cleavage of GSDMD and, correspondingly, cell death in THP-1 macrophages. CRISPR-Cas9 knockout of NLRP3 and GSDMD in THP-1 macrophages confirmed and strongly support the evidence that viral glycoproteins can act as innate immunity triggers. With our study, we decipher key mechanisms of viral pathogenesis by showing that viral glycoproteins potently induce innate immune responses. These insights could be beneficial in vaccine development and provide new impulses for the investigation of vaccine-induced innate immunity.
MeSH term(s)	Cell Line, Tumor ; Cytomegalovirus/immunology ; Hepacivirus/immunology ; Humans ; Immunity, Innate/immunology ; Inflammasomes/immunology ; Interleukin-1beta/biosynthesis ; Interleukin-1beta/immunology ; Macrophages/immunology ; NLR Family, Pyrin Domain-Containing 3 Protein/immunology ; Pyroptosis/immunology ; SARS Virus/immunology ; SARS-CoV-2/immunology ; THP-1 Cells ; Viral Envelope Proteins/immunology ; Viral Fusion Proteins/immunology
Chemical Substances	IL1B protein, human ; Inflammasomes ; Interleukin-1beta ; NLR Family, Pyrin Domain-Containing 3 Protein ; NLRP3 protein, human ; Viral Envelope Proteins ; Viral Fusion Proteins
Language	English
Publishing date	2021-10-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13102076
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Article: Comprehensive Host Cell-Based Screening Assays for Identification of Anti-Virulence Drugs Targeting Pseudomonas aeruginosa and Salmonella Typhimurium

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

Microorganisms. 2020 July 22, v. 8, no. 8

2020

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 (ST), 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 ST 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 ST. 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	Gram-negative bacteria ; Pseudomonas aeruginosa ; Salmonella Typhimurium ; antibiotic resistance ; antibiotics ; bacterial infections ; death ; models ; pathogens ; screening ; type III secretion system ; virulence
Language	English
Dates of publication	2020-0722
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2720891-6
ISSN	2076-2607
ISSN	2076-2607
DOI	10.3390/microorganisms8081096
Database	NAL-Catalogue (AGRICOLA)

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Article: Viral Glycoproteins Induce NLRP3 Inflammasome Activation and Pyroptosis in Macrophages

Eisfeld, Hannah S. / Simonis, Alexander / Winter, Sandra / Chhen, Jason / Ströh, Luisa J. / Krey, Thomas / Koch, Manuel / Theobald, Sebastian J. / Rybniker, Jan

Viruses. 2021 Oct. 15, v. 13, no. 10

2021

Abstract	Infections with viral pathogens are widespread and can cause a variety of different diseases. In-depth knowledge about viral triggers initiating an immune response is necessary to decipher viral pathogenesis. Inflammasomes, as part of the innate immune system, can be activated by viral pathogens. However, viral structural components responsible for inflammasome activation remain largely unknown. Here we analyzed glycoproteins derived from SARS-CoV-1/2, HCMV and HCV, required for viral entry and fusion, as potential triggers of NLRP3 inflammasome activation and pyroptosis in THP-1 macrophages. All tested glycoproteins were able to potently induce NLRP3 inflammasome activation, indicated by ASC-SPECK formation and secretion of cleaved IL-1β. Lytic cell death via gasdermin D (GSDMD), pore formation, and pyroptosis are required for IL-1β release. As a hallmark of pyroptosis, we were able to detect cleavage of GSDMD and, correspondingly, cell death in THP-1 macrophages. CRISPR-Cas9 knockout of NLRP3 and GSDMD in THP-1 macrophages confirmed and strongly support the evidence that viral glycoproteins can act as innate immunity triggers. With our study, we decipher key mechanisms of viral pathogenesis by showing that viral glycoproteins potently induce innate immune responses. These insights could be beneficial in vaccine development and provide new impulses for the investigation of vaccine-induced innate immunity.
Keywords	CRISPR-Cas systems ; glycoproteins ; immune response ; inflammasomes ; innate immunity ; macrophages ; pathogenesis ; pyroptosis ; secretion ; vaccine development
Language	English
Dates of publication	2021-1015
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v13102076
Database	NAL-Catalogue (AGRICOLA)

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Article: Comprehensive Host Cell-Based Screening Assays for Identification of Anti-Virulence Drugs Targeting

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

Microorganisms

2020 Volume 8, Issue 8

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
Language	English
Publishing date	2020-07-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720891-6
ISSN	2076-2607
ISSN	2076-2607
DOI	10.3390/microorganisms8081096
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Book ; Online ; Thesis: Untersuchungen zur funktionellen Relevanz der sauren Sphingomyelinase in der Infektionspathogenese von \(Neisseria\) \(meningitidis\)

Simonis, Alexander [Verfasser] / Schubert-Unkmeir, Alexandra [Gutachter]

2017

Author's details	Alexander Simonis ; Gutachter: Alexandra Schubert-Unkmeir
Keywords	Medizin, Gesundheit ; Medicine, Health
Subject code	sg610
Language	German
Publisher	Universität Würzburg
Publishing place	Würzburg
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Disruption of CSF-1R signaling inhibits growth of AML with inv(16).

Simonis, Alexander / Russkamp, Norman F / Mueller, Jan / Wilk, C Matthias / Wildschut, Mattheus H E / Myburgh, Renier / Wildner-Verhey van Wijk, Nicole / Mueller, Rouven / Balabanov, Stefan / Valk, Peter J M / Theocharides, Alexandre P A / Manz, Markus G

Blood advances

2021 Volume 5, Issue 5, Page(s) 1273–1277

MeSH term(s)	Humans ; Leukemia, Myeloid, Acute ; Receptor Protein-Tyrosine Kinases ; Signal Transduction
Chemical Substances	Receptor Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2021-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2020003125
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Article ; Online: Spleen tyrosine kinase mediates innate and adaptive immune crosstalk in SARS-CoV-2 mRNA vaccination.

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

EMBO molecular medicine

2022 Volume 14, Issue 8, Page(s) e15888

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, ... ...

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.
MeSH term(s)	COVID-19/prevention & control ; COVID-19 Vaccines ; Humans ; Immunity, Innate ; Inflammasomes/metabolism ; Interleukin-1beta ; Intracellular Signaling Peptides and Proteins/genetics ; NLR Family, Pyrin Domain-Containing 3 Protein ; Protein-Tyrosine Kinases/metabolism ; RNA, Messenger/genetics ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/genetics ; Syk Kinase ; Vaccination
Chemical Substances	COVID-19 Vaccines ; Inflammasomes ; Interleukin-1beta ; Intracellular Signaling Peptides and Proteins ; NLR Family, Pyrin Domain-Containing 3 Protein ; RNA, Messenger ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Syk Kinase (EC 2.7.10.2)
Language	English
Publishing date	2022-07-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.202215888
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