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Article ; Online: Ectopic expression of cGAS in

Waanders, Lisette / van der Donk, Lieve E H / Ates, Louis S / Maaskant, Janneke / van Hamme, John L / Eldering, Eric / van Bruggen, Jaco A C / Rietveld, Joanne M / Bitter, Wilbert / Geijtenbeek, Teunis B H / Kuijl, Coenraad P

Journal for immunotherapy of cancer

2023 Volume 11, Issue 4

Abstract: Background: Interferon (IFN)-β induction via activation of the stimulator of interferon genes (STING) pathway has shown promising results in tumor models. STING is activated by cyclic dinucleotides such as cyclic GMP-AMP dinucleotides with ... ...

Abstract	Background: Interferon (IFN)-β induction via activation of the stimulator of interferon genes (STING) pathway has shown promising results in tumor models. STING is activated by cyclic dinucleotides such as cyclic GMP-AMP dinucleotides with phosphodiester linkages 2'-5' and 3'-5' (cGAMPs), that are produced by cyclic GMP-AMP synthetase (cGAS). However, delivery of STING pathway agonists to the tumor site is a challenge. Bacterial vaccine strains have the ability to specifically colonize hypoxic tumor tissues and could therefore be modified to overcome this challenge. Combining high STING-mediated IFN-β levels with the immunostimulatory properties of Methods: We have engineered Results: Expression of cGAS in Conclusion: S. typhimurium
MeSH term(s)	Humans ; Salmonella typhimurium/metabolism ; Ectopic Gene Expression ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism ; Macrophages/metabolism ; Interferon Type I ; Neoplasms/metabolism ; Dendritic Cells/metabolism ; Tumor Microenvironment
Chemical Substances	cyclic guanosine monophosphate-adenosine monophosphate ; Nucleotidyltransferases (EC 2.7.7.-) ; Interferon Type I
Language	English
Publishing date	2023-04-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-005839
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Article ; Online: SARS-CoV-2 suppresses TLR4-induced immunity by dendritic cells via C-type lectin receptor DC-SIGN.

van der Donk, Lieve E H / Bermejo-Jambrina, Marta / van Hamme, John L / Volkers, Mette M W / van Nuenen, Ad C / Kootstra, Neeltje A / Geijtenbeek, Teunis B H

PLoS pathogens

2023 Volume 19, Issue 10, Page(s) e1011735

Abstract: SARS-CoV-2 causes COVID-19, an infectious disease with symptoms ranging from a mild cold to severe pneumonia, inflammation, and even death. Although strong inflammatory responses are a major factor in causing morbidity and mortality, superinfections with ...

Abstract	SARS-CoV-2 causes COVID-19, an infectious disease with symptoms ranging from a mild cold to severe pneumonia, inflammation, and even death. Although strong inflammatory responses are a major factor in causing morbidity and mortality, superinfections with bacteria during severe COVID-19 often cause pneumonia, bacteremia and sepsis. Aberrant immune responses might underlie increased sensitivity to bacteria during COVID-19 but the mechanisms remain unclear. Here we investigated whether SARS-CoV-2 directly suppresses immune responses to bacteria. We studied the functionality of human dendritic cells (DCs) towards a variety of bacterial triggers after exposure to SARS-CoV-2 Spike (S) protein and SARS-CoV-2 primary isolate (hCoV-19/Italy). Notably, pre-exposure of DCs to either SARS-CoV-2 S protein or a SARS-CoV-2 isolate led to reduced type I interferon (IFN) and cytokine responses in response to Toll-like receptor (TLR)4 agonist lipopolysaccharide (LPS), whereas other TLR agonists were not affected. SARS-CoV-2 S protein interacted with the C-type lectin receptor DC-SIGN and, notably, blocking DC-SIGN with antibodies restored type I IFN and cytokine responses to LPS. Moreover, blocking the kinase Raf-1 by a small molecule inhibitor restored immune responses to LPS. These results suggest that SARS-CoV-2 modulates DC function upon TLR4 triggering via DC-SIGN-induced Raf-1 pathway. These data imply that SARS-CoV-2 actively suppresses DC function via DC-SIGN, which might account for the higher mortality rates observed in patients with COVID-19 and bacterial superinfections.
MeSH term(s)	Humans ; SARS-CoV-2/metabolism ; Toll-Like Receptor 4/metabolism ; Lipopolysaccharides/pharmacology ; Lipopolysaccharides/metabolism ; Superinfection ; COVID-19/metabolism ; Lectins, C-Type/metabolism ; Cytokines/metabolism ; Dendritic Cells
Chemical Substances	DC-specific ICAM-3 grabbing nonintegrin ; spike protein, SARS-CoV-2 ; Toll-Like Receptor 4 ; Lipopolysaccharides ; Lectins, C-Type ; Cytokines ; TLR4 protein, human
Language	English
Publishing date	2023-10-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011735
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Article ; Online: An optimized retroviral toolbox for overexpression and genetic perturbation of primary lymphocytes.

van der Donk, Lieve E H / van der Spek, Jet / van Duivenvoorde, Tom / Ten Brink, Marieke S / Geijtenbeek, Teunis B H / Kuijl, Coenraad P / van Heijst, Jeroen W J / Ates, Louis S

Biology open

2022 Volume 11, Issue 2

Abstract: Genetic manipulation of primary lymphocytes is crucial for both clinical purposes and fundamental research. Despite their broad use, we encountered a paucity of data on systematic comparison and optimization of retroviral vectors, the workhorses of ... ...

Abstract	Genetic manipulation of primary lymphocytes is crucial for both clinical purposes and fundamental research. Despite their broad use, we encountered a paucity of data on systematic comparison and optimization of retroviral vectors, the workhorses of genetic modification of primary lymphocytes. Here, we report the construction and validation of a versatile range of retroviral expression vectors. These vectors can be used for the knockdown or overexpression of genes of interest in primary human and murine lymphocytes, in combination with a wide choice of selection and reporter strategies. By streamlining the vector backbone and insert design, these publicly available vectors allow easy interchangeability of the independent building blocks, such as different promoters, fluorescent proteins, surface markers and antibiotic resistance cassettes. We validated these vectors and tested the optimal promoters for in vitro and in vivo overexpression and knockdown of the murine T cell antigen receptor. By publicly sharing these vectors and the data on their optimization, we aim to facilitate genetic modification of primary lymphocytes for researchers entering this field.
MeSH term(s)	Animals ; Genetic Vectors/genetics ; Humans ; Lymphocytes ; Mice ; Promoter Regions, Genetic ; Retroviridae/genetics
Language	English
Publishing date	2022-03-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2632264-X
ISSN	2046-6390 ; 2046-6390
ISSN (online)	2046-6390
ISSN	2046-6390
DOI	10.1242/bio.059032
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Article ; Online: SARS-CoV-2 suppresses TLR4-induced immunity by dendritic cells via C-type lectin receptor DC-SIGN.

Lieve E H van der Donk / Marta Bermejo-Jambrina / John L van Hamme / Mette M W Volkers / Ad C van Nuenen / Neeltje A Kootstra / Teunis B H Geijtenbeek

PLoS Pathogens, Vol 19, Iss 10, p e

2023 Volume 1011735

Abstract	SARS-CoV-2 causes COVID-19, an infectious disease with symptoms ranging from a mild cold to severe pneumonia, inflammation, and even death. Although strong inflammatory responses are a major factor in causing morbidity and mortality, superinfections with bacteria during severe COVID-19 often cause pneumonia, bacteremia and sepsis. Aberrant immune responses might underlie increased sensitivity to bacteria during COVID-19 but the mechanisms remain unclear. Here we investigated whether SARS-CoV-2 directly suppresses immune responses to bacteria. We studied the functionality of human dendritic cells (DCs) towards a variety of bacterial triggers after exposure to SARS-CoV-2 Spike (S) protein and SARS-CoV-2 primary isolate (hCoV-19/Italy). Notably, pre-exposure of DCs to either SARS-CoV-2 S protein or a SARS-CoV-2 isolate led to reduced type I interferon (IFN) and cytokine responses in response to Toll-like receptor (TLR)4 agonist lipopolysaccharide (LPS), whereas other TLR agonists were not affected. SARS-CoV-2 S protein interacted with the C-type lectin receptor DC-SIGN and, notably, blocking DC-SIGN with antibodies restored type I IFN and cytokine responses to LPS. Moreover, blocking the kinase Raf-1 by a small molecule inhibitor restored immune responses to LPS. These results suggest that SARS-CoV-2 modulates DC function upon TLR4 triggering via DC-SIGN-induced Raf-1 pathway. These data imply that SARS-CoV-2 actively suppresses DC function via DC-SIGN, which might account for the higher mortality rates observed in patients with COVID-19 and bacterial superinfections.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	572 ; 616
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: An optimized retroviral toolbox for overexpression and genetic perturbation of primary lymphocytes

Lieve E. H. van der Donk / Jet van der Spek / Tom van Duivenvoorde / Marieke S. ten Brink / Teunis B. H. Geijtenbeek / Coenraad P. Kuijl / Jeroen W. J. van Heijst / Louis S. Ates

Biology Open, Vol 11, Iss

2022 Volume 2

Abstract	Genetic manipulation of primary lymphocytes is crucial for both clinical purposes and fundamental research. Despite their broad use, we encountered a paucity of data on systematic comparison and optimization of retroviral vectors, the workhorses of genetic modification of primary lymphocytes. Here, we report the construction and validation of a versatile range of retroviral expression vectors. These vectors can be used for the knockdown or overexpression of genes of interest in primary human and murine lymphocytes, in combination with a wide choice of selection and reporter strategies. By streamlining the vector backbone and insert design, these publicly available vectors allow easy interchangeability of the independent building blocks, such as different promoters, fluorescent proteins, surface markers and antibiotic resistance cassettes. We validated these vectors and tested the optimal promoters for in vitro and in vivo overexpression and knockdown of the murine T cell antigen receptor. By publicly sharing these vectors and the data on their optimization, we aim to facilitate genetic modification of primary lymphocytes for researchers entering this field.
Keywords	retrovirus ; t cell ; lymphocytes ; overexpression ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	006
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	The Company of Biologists
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SARS-CoV-2 infection activates dendritic cells via cytosolic receptors rather than extracellular TLRs.

van der Donk, Lieve E H / Eder, Julia / van Hamme, John L / Brouwer, Philip J M / Brinkkemper, Mitch / van Nuenen, Ad C / van Gils, Marit J / Sanders, Rogier W / Kootstra, Neeltje A / Bermejo-Jambrina, Marta / Geijtenbeek, Teunis B H

European journal of immunology

2022 Volume 52, Issue 4, Page(s) 646–655

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation, and potentially multiorgan ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation, and potentially multiorgan dysfunction. It remains unclear how SARS-CoV-2 infection leads to immune activation. The Spike (S) protein of SARS-CoV-2 has been suggested to trigger TLR4 and thereby activate immunity. Here, we have investigated the role of TLR4 in SARS-CoV-2 infection and immunity. Neither exposure of isolated S protein, SARS-CoV-2 pseudovirus nor primary SARS-CoV-2 isolate induced TLR4 activation in a TLR4-expressing cell line. Human monocyte-derived DCs express TLR4 but not angiotensin converting enzyme 2 (ACE2), and DCs were not infected by SARS-CoV-2. Notably, neither S protein nor SARS-CoV-2 induced DC maturation or cytokines, indicating that both S protein and SARS-CoV-2 virus particles do not trigger extracellular TLRs including TLR4. Ectopic expression of ACE2 in DCs led to efficient infection by SARS-CoV-2 and, strikingly, efficient type I IFN and cytokine responses. These data strongly suggest that not extracellular TLRs but intracellular viral sensors are key players in sensing SARS-CoV-2. These data imply that SARS-CoV-2 escapes direct sensing by TLRs, which might underlie the lack of efficient immunity to SARS-CoV-2 early during infection.
MeSH term(s)	COVID-19/immunology ; Cell Line ; Dendritic Cells/immunology ; Humans ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/immunology ; Toll-Like Receptor 4/immunology
Chemical Substances	Spike Glycoprotein, Coronavirus ; TLR4 protein, human ; Toll-Like Receptor 4 ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-02-16
Publishing country	Germany
Document type	Journal Article
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202149656
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Article ; Online: Antibodies against SARS-CoV-2 control complement-induced inflammatory responses to SARS-CoV-2

Bermejo-Jambrina, Marta / van der Donk, Lieve E.H. / van Hamme, John L. / Wilflingseder, Doris / de Bree, Godelieve / Prins, Maria / de Jong, Menno / Nieuwkerk, Pythia / van Gils, Marit J. / Kootstra, Neeltje A. / Geijtenbeek, Teunis B.H.

bioRxiv

Abstract: Dysregulated immune responses contribute to pathogenesis of COVID-19 leading to uncontrolled and exaggerated inflammation observed during severe COVID-19. However, it remains unclear how immunity to SARS-CoV-2 is induced and subsequently controlled. ... ...

Abstract	Dysregulated immune responses contribute to pathogenesis of COVID-19 leading to uncontrolled and exaggerated inflammation observed during severe COVID-19. However, it remains unclear how immunity to SARS-CoV-2 is induced and subsequently controlled. Notably, here we have uncovered an important role for complement in the induction of innate and adaptive immunity to SARS-CoV-2. Complement rapidly opsonized SARS-CoV-2 via the lectin pathway. Complement-opsonized SARS-CoV-2 efficiently interacted with dendritic cells (DCs), inducing type I IFN and pro-inflammatory cytokine responses, which were inhibited by antibodies against the complement receptors (CR)3 and CR4. These data suggest that complement is important in inducing immunity via DCs in the acute phase against SARS-CoV-2. Strikingly, serum from COVID-19 patients as well as monoclonal antibodies against SARS-CoV-2 attenuated innate and adaptive immunity induced by complement-opsonized SARS-CoV-2. Blocking the FcyRII, CD32, restored complement-induced immunity. These data strongly suggest that complement opsonization of SARS-CoV-2 is important for inducing innate and adaptive immunity to SARS-CoV-2. Subsequent induction of antibody responses is important to limit the immune responses and restore immune homeostasis. These data suggest that dysregulation in complement and FcyRII signalling might underlie mechanisms causing severe COVID-19.
Keywords	covid19
Language	English
Publishing date	2023-05-30
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.05.29.542735
Database	COVID19

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Article ; Online: Separate signaling events control TCR downregulation and T cell activation in primary human T cells.

van der Donk, Lieve E H / Ates, Louis S / van der Spek, Jet / Tukker, Laura M / Geijtenbeek, Teunis B H / van Heijst, Jeroen W J

Immunity, inflammation and disease

2020 Volume 9, Issue 1, Page(s) 223–238

Abstract: Introduction: T-cell antigen receptor (TCR) interaction with cognate peptide:MHC complexes trigger clustering of TCR:CD3 complexes and signal transduction. Triggered TCR:CD3 complexes are rapidly internalized and degraded in a process called ligand- ... ...

Abstract	Introduction: T-cell antigen receptor (TCR) interaction with cognate peptide:MHC complexes trigger clustering of TCR:CD3 complexes and signal transduction. Triggered TCR:CD3 complexes are rapidly internalized and degraded in a process called ligand-induced TCR downregulation. Classic studies in immortalized T-cell lines have revealed a major role for the Src family kinase Lck in TCR downregulation. However, to what extent a similar mechanism operates in primary human T cells remains unclear. Methods: Here, we developed an anti-CD3-mediated TCR downregulation assay, in which T-cell gene expression in primary human T cells can be knocked down by microRNA constructs. In parallel, we used CRISPR/Cas9-mediated knockout in Jurkat cells for validation experiments. Results: We efficiently knocked down the expression of tyrosine kinases Lck, Fyn, and ZAP70, and found that, whereas this impaired T cell activation and effector function, TCR downregulation was not affected. Although TCR downregulation was marginally inhibited by the simultaneous knockdown of Lck and Fyn, its full abrogation required broad-acting tyrosine kinase inhibitors. Conclusions: These data suggest that there is substantial redundancy in the contribution of individual tyrosine kinases to TCR downregulation in primary human T cells. Our results highlight that TCR downregulation and T cell activation are controlled by different signaling events and illustrate the need for further research to untangle these processes.
MeSH term(s)	Down-Regulation ; Humans ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism ; Phosphorylation ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-fyn/genetics ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Signal Transduction
Chemical Substances	Proto-Oncogene Proteins ; Receptors, Antigen, T-Cell ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (EC 2.7.10.2) ; Proto-Oncogene Proteins c-fyn (EC 2.7.10.2)
Language	English
Publishing date	2020-12-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2050-4527
ISSN (online)	2050-4527
DOI	10.1002/iid3.383
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Article ; Online: Platelet Btk is Required for Maintaining Lung Vascular Integrity during Murine Pneumococcal Pneumosepsis.

de Porto, Alexander P N A / Claushuis, Theodora A M / van der Donk, Lieve E H / de Beer, Regina / de Boer, Onno J / Florquin, Sandrine / Roelofs, Joris J T H / Hendriks, Rudi W / van der Poll, Tom / Van't Veer, Cornelis / de Vos, Alex F

Thrombosis and haemostasis

2019 Volume 119, Issue 6, Page(s) 930–940

Abstract: Platelet Bruton's tyrosine kinase (Btk) is an essential signalling protein for the collagen receptor glycoprotein VI (GPVI) and podoplanin receptor C-type-lectin-like receptor-2, which are platelet receptors implicated in the maintenance of vascular ... ...

Abstract	Platelet Bruton's tyrosine kinase (Btk) is an essential signalling protein for the collagen receptor glycoprotein VI (GPVI) and podoplanin receptor C-type-lectin-like receptor-2, which are platelet receptors implicated in the maintenance of vascular integrity during inflammation. Moreover, platelets, platelet GPVI and Btk are important for host defence during murine bacterial pneumosepsis. The aim of this study was to determine the role of platelet Btk in vascular integrity and host defence during murine pneumosepsis caused by the common human pathogens
MeSH term(s)	Agammaglobulinaemia Tyrosine Kinase/genetics ; Agammaglobulinaemia Tyrosine Kinase/metabolism ; Animals ; Blood Platelets/physiology ; Disease Models, Animal ; Hemorrhage ; Humans ; Immunity ; Klebsiella pneumoniae/physiology ; Lung/blood supply ; Lung/pathology ; Male ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Knockout ; Platelet Aggregation/genetics ; Platelet Membrane Glycoproteins/metabolism ; Pneumonia, Pneumococcal/genetics ; Pneumonia, Pneumococcal/metabolism ; Regional Blood Flow ; Sepsis/metabolism ; Signal Transduction ; Streptococcus pneumoniae/physiology
Chemical Substances	Gp38 protein, mouse ; Membrane Glycoproteins ; Platelet Membrane Glycoproteins ; platelet membrane glycoprotein VI ; Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2)
Language	English
Publishing date	2019-03-14
Publishing country	Germany
Document type	Journal Article
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1055/s-0039-1681046
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Uh III Zs.192: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: SARS-CoV-2 infection activates dendritic cells via cytosolic receptors rather than extracellular TLRs

van der Donk, Lieve E.H. / Eder, Julia / van Hamme, John L. / Brouwer, Philip J.M. / Brinkkemper, Mitch / van Nuenen, Ad C. / van Gils, Marit J. / Sanders, Rogier W. / Kootstra, Neeltje A. / Bermejo-Jambrina, Marta / Geijtenbeek, Teunis B.H.

bioRxiv

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation and potentially multi-organ dysfunction. It remains unclear whether SARS-CoV-2 is sensed by pattern recognition receptors (PRRs) leading to immune activation. Several studies suggest that the Spike (S) protein of SARS-CoV-2 might interact with Toll-like receptor 4 (TLR4) and thereby activate immunity. Here we have investigated the role of TLR4 in SARS-CoV-2 infection and immunity. Neither exposure of isolated S protein, SARS-CoV-2 pseudovirus nor a primary SARS-CoV-2 isolate induced TLR4 activation in a TLR4-expressing cell line. Human monocyte-derived dendritic cells (DCs) express TLR4 but not ACE2, and DCs were not infected by a primary SARS-CoV-2 isolate. Notably, neither S protein nor the primary SARS-CoV-2 isolate induced DC maturation or cytokines, indicating that both S protein and SARS-CoV-2 virus particles do not trigger extracellular TLRs, including TLR4. Ectopic expression of ACE2 in DCs led to efficient infection by SARS-CoV-2. Strikingly, infection of ACE2-positive DCs induced type I IFN and cytokine responses, which was inhibited by antibodies against ACE2. These data strongly suggest that not extracellular TLRs but intracellular viral sensors are key players in sensing SARS-CoV-2. These data imply that SARS-CoV-2 escapes direct sensing by TLRs, which might underlie the lack of efficient immunity to SARS-CoV-2 early during infection.
Keywords	covid19
Language	English
Publishing date	2021-09-03
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.09.02.458667
Database	COVID19

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