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4. NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections

Author

Klabunde, Björn, Wesener, André, Bertrams, Wilhelm, Beinborn, Isabell, Paczia, Nicole, Surmann, Kristin, Blankenburg, Sascha, Wilhelm, Jochen, Serrania, Javier, Knoops, Kèvin, Elsayed, Eslam M., Laakmann, Katrin, Jung, Anna Lena, Kirschbaum, Andreas, Hammerschmidt, Sven, Alshaar, Belal, Gisch, Nicolas, Abu Mraheil, Mobarak, Becker, Anke, Völker, Uwe, Vollmeister, Evelyn, Benedikter, Birke J., and Schmeck, Bernd

Published
2023
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7. Intercellular transfer of miR-200c-3p impairs the angiogenic capacity of cardiac endothelial cells

Author

Ottaviani, Lara, Juni, Rio P., de Abreu, Ricardo C., Sansonetti, Marida, Sampaio-Pinto, Vasco, Halkein, Julie, Hegenbarth, Jana C., Ring, Nadja, Knoops, Kevin, Kocken, Jordy M.M., Jesus, Carlos de, Ernault, Auriane C., el Azzouzi, Hamid, Rühle, Frank, Olieslagers, Servé, Fernandes, Hugo, Ferreira, Lino, Braga, Luca, Stoll, Monika, Nascimento, Diana S., de Windt, Leon J., and da Costa Martins, Paula A.

Published
2022
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8. Antenatal Ureaplasma Infection Causes Colonic Mucus Barrier Defects: Implications for Intestinal Pathologies

Author

van Gorp, Charlotte, primary, de Lange, Ilse H., additional, Hütten, Matthias C., additional, López-Iglesias, Carmen, additional, Massy, Kimberly R. I., additional, Kessels, Lilian, additional, Knoops, Kèvin, additional, Cuijpers, Iris, additional, Sthijns, Mireille M. J. P. E., additional, Troost, Freddy J., additional, van Gemert, Wim G., additional, Spiller, Owen B., additional, Birchenough, George M. H., additional, Zimmermann, Luc J. I., additional, and Wolfs, Tim G. A. M., additional

Published
2024
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12. An organoid‐derived bronchioalveolar model for SARS‐CoV‐2 infection of human alveolar type II‐like cells

Author

Lamers, Mart M, van der Vaart, Jelte, Knoops, Kèvin, Riesebosch, Samra, Breugem, Tim I, Mykytyn, Anna Z, Beumer, Joep, Schipper, Debby, Bezstarosti, Karel, Koopman, Charlotte D, Groen, Nathalie, Ravelli, Raimond B G, Duimel, Hans Q, Demmers, Jeroen A A, Verjans, Georges M G M, Koopmans, Marion P G, Muraro, Mauro J, Peters, Peter J, Clevers, Hans, and Haagmans, Bart L

Published
2021
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13. Polymer film-based microwell array platform for long-term culture and research of human bronchial organoids

Author

Baptista, Danielle, primary, Tahmasebi Birgani, Zeinab, additional, Widowski, Helene, additional, Passanha, Fiona, additional, Stylianidis, Vasili, additional, Knoops, Kèvin, additional, Gubbins, Eva, additional, Iriondo, Cinta, additional, Skarp, Kari-Pekka, additional, Rottier, Robbert J., additional, Wolfs, Tim G., additional, van Blitterswijk, Clemens, additional, LaPointe, Vanessa, additional, Habibović, Pamela, additional, Reynaert, Niki L., additional, Giselbrecht, Stefan, additional, and Truckenmüller, Roman, additional

Published
2023
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14. Polymer film-based microwell array platform for long-term culture and research of human bronchial organoids

Author

Baptista, Danielle, Tahmasebi Birgani, Zeinab, Widowski, Helene, Passanha, Fiona, Stylianidis, Vasili, Knoops, Kèvin, Gubbins, Eva, Iriondo, Cinta, Skarp, Kari Pekka, Rottier, Robbert J., Wolfs, Tim G., van Blitterswijk, Clemens, LaPointe, Vanessa, Habibović, Pamela, Reynaert, Niki L., Giselbrecht, Stefan, Truckenmüller, Roman, Baptista, Danielle, Tahmasebi Birgani, Zeinab, Widowski, Helene, Passanha, Fiona, Stylianidis, Vasili, Knoops, Kèvin, Gubbins, Eva, Iriondo, Cinta, Skarp, Kari Pekka, Rottier, Robbert J., Wolfs, Tim G., van Blitterswijk, Clemens, LaPointe, Vanessa, Habibović, Pamela, Reynaert, Niki L., Giselbrecht, Stefan, and Truckenmüller, Roman

Abstract

The culture of lung organoids relies on drops of basement membrane matrices. This comes with limitations, for example, concerning the microscopic monitoring and imaging of the organoids in the drops. Also, the culture technique is not easily compatible with micromanipulations of the organoids. In this study, we investigated the feasibility of the culture of human bronchial organoids in defined x-, y- and z-positions in a polymer film-based microwell array platform. The circular microwells have thin round/U-bottoms. For this, single cells are first precultured in drops of basement membrane extract (BME). After they form cell clusters or premature organoids, the preformed structures are then transferred into the microwells in a solution of 50% BME in medium. There, the structures can be cultured toward differentiated and mature organoids for several weeks. The organoids were characterized by bright-field microscopy for size growth and luminal fusion over time, by scanning electron microscopy for overall morphology, by transmission electron microscopy for the existence of microvilli and cilia, by video microscopy for beating cilia and swirling fluid, by live-cell imaging, by fluorescence microscopy for the expression of cell-specific markers and for proliferating and apoptotic cells, and by ATP measurement for extended cell viability. Finally, we demonstrated the eased micromanipulation of the organoids in the microwells by the example of their microinjection.

Published
2023

15. NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections.

Author

Klabunde, Björn, Wesener, André, Bertrams, Wilhelm, Beinborn, Isabell, Paczia, Nicole, Surmann, Kristin, Blankenburg, Sascha, Wilhelm, Jochen, Serrania, Javier, Knoops, Kèvin, Elsayed, Eslam M., Laakmann, Katrin, Jung, Anna Lena, Kirschbaum, Andreas, Hammerschmidt, Sven, Alshaar, Belal, Gisch, Nicolas, Abu Mraheil, Mobarak, Becker, Anke, and Völker, Uwe

Subjects
NAD (Coenzyme), NICOTINAMIDE, RESPIRATORY infections, BACTERIAL metabolism, STREPTOCOCCUS pneumoniae, STREPTOCOCCAL diseases, METABOLISM
Abstract

Lower respiratory tract infections caused by Streptococcus pneumoniae (Spn) are a leading cause of death globally. Here we investigate the bronchial epithelial cellular response to Spn infection on a transcriptomic, proteomic and metabolic level. We found the NAD+ salvage pathway to be dysregulated upon infection in a cell line model, primary human lung tissue and in vivo in rodents, leading to a reduced production of NAD+. Knockdown of NAD+ salvage enzymes (NAMPT, NMNAT1) increased bacterial replication. NAD+ treatment of Spn inhibited its growth while growth of other respiratory pathogens improved. Boosting NAD+ production increased NAD+ levels in immortalized and primary cells and decreased bacterial replication upon infection. NAD+ treatment of Spn dysregulated the bacterial metabolism and reduced intrabacterial ATP. Enhancing the bacterial ATP metabolism abolished the antibacterial effect of NAD+. Thus, we identified the NAD+ salvage pathway as an antibacterial pathway in Spn infections, predicting an antibacterial mechanism of NAD+. Streptococcus pneumoniae is a common cause of lower respiratory tract infection. Here, Klabunde et al. present a transcriptomic, metabolomic and proteomic characterisation of the bronchial epithelial cell response to infection and show that NAD+ has a role in controlling bacterial replication. [ABSTRACT FROM AUTHOR]

Published
2023
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19. Mycobacteria-host interactions in human bronchiolar airway organoids

Author

Iakobachvili, Nino, Leon-Icaza, Stephen Adonai, Knoops, Kèvin, Sachs, Norman, Mazères, Serge, Simeone, Roxane, Peixoto, Antonio, Bernard, Célia, Murris-Espin, Marlène, Mazières, Julien, Cam, Kaymeuang, Chalut, Christian, Guilhot, Christophe, López-Iglesias, Carmen, Ravelli, Raimond B G, Neyrolles, Olivier, Meunier, Etienne, Lugo-Villarino, Geanncarlo, Clevers, Hans, Cougoule, Céline, Peters, Peter J, Iakobachvili, Nino, Leon-Icaza, Stephen Adonai, Knoops, Kèvin, Sachs, Norman, Mazères, Serge, Simeone, Roxane, Peixoto, Antonio, Bernard, Célia, Murris-Espin, Marlène, Mazières, Julien, Cam, Kaymeuang, Chalut, Christian, Guilhot, Christophe, López-Iglesias, Carmen, Ravelli, Raimond B G, Neyrolles, Olivier, Meunier, Etienne, Lugo-Villarino, Geanncarlo, Clevers, Hans, Cougoule, Céline, and Peters, Peter J

Abstract

Respiratory infections remain a major global health concern. Tuberculosis is one of the top 10 causes of death worldwide, while infections with Non-Tuberculous Mycobacteria are rising globally. Recent advances in human tissue modeling offer a unique opportunity to grow different human "organs" in vitro, including the human airway, that faithfully recapitulates lung architecture and function. Here, we have explored the potential of human airway organoids (AOs) as a novel system in which to assess the very early steps of mycobacterial infection. We reveal that Mycobacterium tuberculosis (Mtb) and Mycobacterium abscessus (Mabs) mainly reside as extracellular bacteria and infect epithelial cells with very low efficiency. While the AO microenvironment was able to control, but not eliminate Mtb, Mabs thrives. We demonstrate that AOs responded to infection by modulating cytokine, antimicrobial peptide, and mucin gene expression. Given the importance of myeloid cells in mycobacterial infection, we co-cultured infected AOs with human monocyte-derived macrophages and found that these cells interact with the organoid epithelium. We conclude that adult stem cell (ASC)-derived AOs can be used to decipher very early events of mycobacteria infection in human settings thus offering new avenues for fundamental and therapeutic research.

Published
2022

20. Mycobacteria–host interactions in human bronchiolar airway organoids

Author

Cancer, CMM, Hubrecht Institute with UMC, Iakobachvili, Nino, Leon-Icaza, Stephen Adonai, Knoops, Kèvin, Sachs, Norman, Mazères, Serge, Simeone, Roxane, Peixoto, Antonio, Bernard, Célia, Murris-Espin, Marlène, Mazières, Julien, Cam, Kaymeuang, Chalut, Christian, Guilhot, Christophe, López-Iglesias, Carmen, Ravelli, Raimond B.G., Neyrolles, Olivier, Meunier, Etienne, Lugo-Villarino, Geanncarlo, Clevers, Hans, Cougoule, Céline, Peters, Peter J., Cancer, CMM, Hubrecht Institute with UMC, Iakobachvili, Nino, Leon-Icaza, Stephen Adonai, Knoops, Kèvin, Sachs, Norman, Mazères, Serge, Simeone, Roxane, Peixoto, Antonio, Bernard, Célia, Murris-Espin, Marlène, Mazières, Julien, Cam, Kaymeuang, Chalut, Christian, Guilhot, Christophe, López-Iglesias, Carmen, Ravelli, Raimond B.G., Neyrolles, Olivier, Meunier, Etienne, Lugo-Villarino, Geanncarlo, Clevers, Hans, Cougoule, Céline, and Peters, Peter J.

Published
2022

23. Mycobacteria–host interactions in human bronchiolar airway organoids

Author

Iakobachvili, Nino, primary, Leon‐Icaza, Stephen Adonai, additional, Knoops, Kèvin, additional, Sachs, Norman, additional, Mazères, Serge, additional, Simeone, Roxane, additional, Peixoto, Antonio, additional, Bernard, Célia, additional, Murris‐Espin, Marlène, additional, Mazières, Julien, additional, Cam, Kaymeuang, additional, Chalut, Christian, additional, Guilhot, Christophe, additional, López‐Iglesias, Carmen, additional, Ravelli, Raimond B. G., additional, Neyrolles, Olivier, additional, Meunier, Etienne, additional, Lugo‐Villarino, Geanncarlo, additional, Clevers, Hans, additional, Cougoule, Céline, additional, and Peters, Peter J., additional

Published
2021
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24. Mycobacteria-host interactions in human bronchiolar airway organoids

Author

Iakobachvili, Nino, Leon-Icaza, Stephen Adonai, Knoops, Kèvin, Sachs, Norman, Mazères, Serge, Simeone, Roxane, Peixoto, Antonio, Bernard, Célia, Murris-Espin, Marlène, Mazières, Julien, Cam, Kaymeuang, Chalut, Christian, Guilhot, Christophe, López-Iglesias, Carmen, Ravelli, Raimond B G, Neyrolles, Olivier, Meunier, Etienne, Lugo-Villarino, Geanncarlo, Clevers, Hans, Cougoule, Céline, Peters, Peter J, Iakobachvili, Nino, Leon-Icaza, Stephen Adonai, Knoops, Kèvin, Sachs, Norman, Mazères, Serge, Simeone, Roxane, Peixoto, Antonio, Bernard, Célia, Murris-Espin, Marlène, Mazières, Julien, Cam, Kaymeuang, Chalut, Christian, Guilhot, Christophe, López-Iglesias, Carmen, Ravelli, Raimond B G, Neyrolles, Olivier, Meunier, Etienne, Lugo-Villarino, Geanncarlo, Clevers, Hans, Cougoule, Céline, and Peters, Peter J

Abstract

Respiratory infections remain a major global health concern. Tuberculosis is one of the top 10 causes of death worldwide, while infections with Non-Tuberculous Mycobacteria are rising globally. Recent advances in human tissue modeling offer a unique opportunity to grow different human "organs" in vitro, including the human airway, that faithfully recapitulates lung architecture and function. Here, we have explored the potential of human airway organoids (AOs) as a novel system in which to assess the very early steps of mycobacterial infection. We reveal that Mycobacterium tuberculosis (Mtb) and Mycobacterium abscessus (Mabs) mainly reside as extracellular bacteria and infect epithelial cells with very low efficiency. While the AO microenvironment was able to control, but not eliminate Mtb, Mabs thrives. We demonstrate that AOs responded to infection by modulating cytokine, antimicrobial peptide, and mucin gene expression. Given the importance of myeloid cells in mycobacterial infection, we co-cultured infected AOs with human monocyte-derived macrophages and found that these cells interact with the organoid epithelium. We conclude that adult stem cell (ASC)-derived AOs can be used to decipher very early events of mycobacteria infection in human settings thus offering new avenues for fundamental and therapeutic research.

Published
2021

25. Alternative glycosylation controls endoplasmic reticulum dynamics and tubular extension in mammalian cells

Author

Kerselidou, Despoina, Dohai, Bushra Saeed, Nelson, David R., Daakour, Sarah, De Cock, Nicolas, Al Oula Hassoun, Zahra, Kim, Dae-Kyum, Olivet, Julien, El Assal, Diana C., Jaiswal, Ashish, Alzahmi, Amnah, Saha, Deeya, Pain, Charlotte, Matthijssens, Filip, Lemaitre, Pierre, Herfs, Michael, Chapuis, Julien, Ghesquiere, Bart, Vertommen, Didier, Kriechbaumer, Verena, Knoops, Kèvin, Lopez-Iglesias, Carmen, van Zandvoort, Marc, Lambert, Jean-Charles, Hanson, Julien, Desmet, Christophe, Thiry, Marc, Lauersen, Kyle J., Vidal, Marc, Van Vlierberghe, Pieter, Dequiedt, Franck, Salehi-Ashtiani, Kourosh, Twizere, Jean-Claude, Kerselidou, Despoina, Dohai, Bushra Saeed, Nelson, David R., Daakour, Sarah, De Cock, Nicolas, Al Oula Hassoun, Zahra, Kim, Dae-Kyum, Olivet, Julien, El Assal, Diana C., Jaiswal, Ashish, Alzahmi, Amnah, Saha, Deeya, Pain, Charlotte, Matthijssens, Filip, Lemaitre, Pierre, Herfs, Michael, Chapuis, Julien, Ghesquiere, Bart, Vertommen, Didier, Kriechbaumer, Verena, Knoops, Kèvin, Lopez-Iglesias, Carmen, van Zandvoort, Marc, Lambert, Jean-Charles, Hanson, Julien, Desmet, Christophe, Thiry, Marc, Lauersen, Kyle J., Vidal, Marc, Van Vlierberghe, Pieter, Dequiedt, Franck, Salehi-Ashtiani, Kourosh, and Twizere, Jean-Claude

Abstract

The endoplasmic reticulum (ER) is a central eukaryotic organelle with a tubular network made of hairpin proteins linked by hydrolysis of GTP nucleotides. Among post-translational modifications initiated at the ER level, glycosylation is the most common reaction. However, our understanding of the impact of glycosylation on the ER structure remains unclear. Here, we show that Exostosin-1 (EXT1) glycosyltransferase, an enzyme involved in N-glycosylation, is a key regulator of the ER morphology and dynamics. We have integrated multi-omics data and super-resolution imaging to characterize the broad effect of EXT1 inactivation, including the ER shape-dynamics-function relationships in mammalian cells. We have observed that inactivating EXT1 induces cell enlargement and enhances metabolic switches such as protein secretion. In particular, suppressing EXT1 in mouse thymocytes causes developmental dysfunctions associated with the ER network extension. Finally, our data illuminate the physical and functional aspects of the ER proteome-glycome-lipidome-structure axis, with implications in biotechnology and medicine.

Published
2021

26. Alternative glycosylation controls endoplasmic reticulum dynamics and tubular extension in mammalian cells

Author

UCL - SSS/DDUV/PHOS - Protein phosphorylation, Kerselidou, Despoina, Dohai, Bushra Saeed, Nelson, David R., Daakour, Sarah, De Cock, Nicolas, Hassoun, Zahra Al Oula, Kim, Dae-Kyum, Olivet, Julien, El Assal, Diana C., Jaiswal, Ashish, Alzahmi, Amnah, Saha, Deeya, Pain, Charlotte, Matthijssens, Filip, Lemaitre, Pierre, Herfs, Michael, Chapuis, Julien, Ghesquiere, Bart, Vertommen, Didier, Kriechbaumer, Verena, Knoops, Kèvin, Lopez-Iglesias, Carmen, van Zandvoort, Marc, Lambert, Jean-Charles, Hanson, Julien, Desmet, Christophe, Thiry, Marc, Lauersen, Kyle J., Vidal, Marc, Van Vlierberghe, Pieter, Dequiedt, Franck, Salehi-Ashtiani, Kourosh, Twizere, Jean-Claude, UCL - SSS/DDUV/PHOS - Protein phosphorylation, Kerselidou, Despoina, Dohai, Bushra Saeed, Nelson, David R., Daakour, Sarah, De Cock, Nicolas, Hassoun, Zahra Al Oula, Kim, Dae-Kyum, Olivet, Julien, El Assal, Diana C., Jaiswal, Ashish, Alzahmi, Amnah, Saha, Deeya, Pain, Charlotte, Matthijssens, Filip, Lemaitre, Pierre, Herfs, Michael, Chapuis, Julien, Ghesquiere, Bart, Vertommen, Didier, Kriechbaumer, Verena, Knoops, Kèvin, Lopez-Iglesias, Carmen, van Zandvoort, Marc, Lambert, Jean-Charles, Hanson, Julien, Desmet, Christophe, Thiry, Marc, Lauersen, Kyle J., Vidal, Marc, Van Vlierberghe, Pieter, Dequiedt, Franck, Salehi-Ashtiani, Kourosh, and Twizere, Jean-Claude

Abstract

The endoplasmic reticulum (ER) is a central eukaryotic organelle with a tubular network made of hairpin proteins linked by hydrolysis of guanosine triphosphate nucleotides. Among posttranslational modifications initiated at the ER level, glycosylation is the most common reaction. However, our understanding of the impact of glycosylation on the ER structure remains unclear. Here, we show that exostosin-1 (EXT1) glycosyltransferase, an enzyme involved in N-glycosylation, is a key regulator of ER morphology and dynamics. We have integrated multiomics and superresolution imaging to characterize the broad effect of EXT1 inactivation, including the ER shape-dynamics-function relationships in mammalian cells. We have observed that inactivating EXT1 induces cell enlargement and enhances metabolic switches such as protein secretion. In particular, suppressing EXT1 in mouse thymocytes causes developmental dysfunctions associated with the ER network extension. Last, our data illuminate the physical and functional aspects of the ER proteome-glycome-lipidome structure axis, with implications in biotechnology and medicine

Published
2021

27. Adult mouse and human organoids derived from thyroid follicular cells and modeling of Graves’ hyperthyroidism

Author

CDL Patiëntenzorg MI, Infection & Immunity, MS CGO, Regenerative Medicine and Stem Cells, Cancer, CDL Staf Patiëntenzorg KC, Other research (not in main researchprogram), Endocrinologie patientenzorg, Brain, Child Health, Heelkunde Opleiding, CMM Sectie Molecular Cancer Research, van der Vaart, Jelte, Bosmans, Lynn, Sijbesma, Stijn F, Knoops, Kèvin, van de Wetering, Willine J, Otten, Henny G, Begthel, Harry, Borel Rinkes, Inne H M, Korving, Jeroen, Lentjes, Eef G W M, Lopez-Iglesias, Carmen, Peters, Peter J, van Santen, Hanneke M, Vriens, Menno R, Clevers, Hans, CDL Patiëntenzorg MI, Infection & Immunity, MS CGO, Regenerative Medicine and Stem Cells, Cancer, CDL Staf Patiëntenzorg KC, Other research (not in main researchprogram), Endocrinologie patientenzorg, Brain, Child Health, Heelkunde Opleiding, CMM Sectie Molecular Cancer Research, van der Vaart, Jelte, Bosmans, Lynn, Sijbesma, Stijn F, Knoops, Kèvin, van de Wetering, Willine J, Otten, Henny G, Begthel, Harry, Borel Rinkes, Inne H M, Korving, Jeroen, Lentjes, Eef G W M, Lopez-Iglesias, Carmen, Peters, Peter J, van Santen, Hanneke M, Vriens, Menno R, and Clevers, Hans

Published
2021

28. Modelling of primary ciliary dyskinesia using patient-derived airway organoids

Author

Hubrecht Institute with UMC, van der Vaart, Jelte, Böttinger, Lena, Geurts, Maarten H., van de Wetering, Willine J., Knoops, Kèvin, Sachs, Norman, Begthel, Harry, Korving, Jeroen, Lopez-Iglesias, Carmen, Peters, Peter J., Eitan, Kerem, Gileles-Hillel, Alex, Clevers, Hans, Hubrecht Institute with UMC, van der Vaart, Jelte, Böttinger, Lena, Geurts, Maarten H., van de Wetering, Willine J., Knoops, Kèvin, Sachs, Norman, Begthel, Harry, Korving, Jeroen, Lopez-Iglesias, Carmen, Peters, Peter J., Eitan, Kerem, Gileles-Hillel, Alex, and Clevers, Hans

Published
2021

29. An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells

Author

Medische Fysiologie, CMM Sectie Molecular Cancer Research, Child Health, Regenerative Medicine and Stem Cells, Cancer, Hubrecht Institute with UMC, Lamers, Mart M, van der Vaart, Jelte, Knoops, Kèvin, Riesebosch, Samra, Breugem, Tim I, Mykytyn, Anna Z, Beumer, Joep, Schipper, Debby, Bezstarosti, Karel, Koopman, Charlotte D, Groen, Nathalie, Ravelli, Raimond B G, Duimel, Hans Q, Demmers, Jeroen A A, Verjans, Georges M G M, Koopmans, Marion P G, Muraro, Mauro J, Peters, Peter J, Clevers, Hans, Haagmans, Bart L, Medische Fysiologie, CMM Sectie Molecular Cancer Research, Child Health, Regenerative Medicine and Stem Cells, Cancer, Hubrecht Institute with UMC, Lamers, Mart M, van der Vaart, Jelte, Knoops, Kèvin, Riesebosch, Samra, Breugem, Tim I, Mykytyn, Anna Z, Beumer, Joep, Schipper, Debby, Bezstarosti, Karel, Koopman, Charlotte D, Groen, Nathalie, Ravelli, Raimond B G, Duimel, Hans Q, Demmers, Jeroen A A, Verjans, Georges M G M, Koopmans, Marion P G, Muraro, Mauro J, Peters, Peter J, Clevers, Hans, and Haagmans, Bart L

Published
2021

30. Alternative glycosylation controls endoplasmic reticulum dynamics and tubular extension in mammalian cells

Author

Kerselidou, Despoina, primary, Dohai, Bushra Saeed, additional, Nelson, David R., additional, Daakour, Sarah, additional, De Cock, Nicolas, additional, Hassoun, Zahra Al Oula, additional, Kim, Dae-Kyum, additional, Olivet, Julien, additional, El Assal, Diana C., additional, Jaiswal, Ashish, additional, Alzahmi, Amnah, additional, Saha, Deeya, additional, Pain, Charlotte, additional, Matthijssens, Filip, additional, Lemaitre, Pierre, additional, Herfs, Michael, additional, Chapuis, Julien, additional, Ghesquiere, Bart, additional, Vertommen, Didier, additional, Kriechbaumer, Verena, additional, Knoops, Kèvin, additional, Lopez-Iglesias, Carmen, additional, van Zandvoort, Marc, additional, Lambert, Jean-Charles, additional, Hanson, Julien, additional, Desmet, Christophe, additional, Thiry, Marc, additional, Lauersen, Kyle J., additional, Vidal, Marc, additional, Van Vlierberghe, Pieter, additional, Dequiedt, Franck, additional, Salehi-Ashtiani, Kourosh, additional, and Twizere, Jean-Claude, additional

Published
2021
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31. SARS-CoV-2 productively infects human gut enterocytes

Author

Lamers, Mart M., Beumer, Joep, van der Vaart, Jelte, Knoops, Kèvin, Puschhof, Jens, Breugem, Tim I., and Ravelli, Raimond B. G.

Subjects
viruses, fungi, virus diseases, skin and connective tissue diseases, respiratory tract diseases
Abstract

The virus severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) can cause coronavirus disease 2019 (COVID-19), an influenza-like disease that is primarily thought to infect the lungs with transmission via the respiratory route. However, clinical evidence suggests that the intestine may present another viral target organ. Indeed, the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes. In human small intestinal organoids (hSIOs), enterocytes were readily infected by SARS-CoV and SARS-CoV-2 as demonstrated by confocal- and electron-microscopy.

Published
2020

32. SARS-CoV-2 productively infects human gut enterocytes

Author

Lamers, Mart M, Beumer, Joep, van der Vaart, Jelte, Knoops, Kèvin, Puschhof, Jens, Breugem, Tim I, Ravelli, Raimond B G, Paul van Schayck, J, Mykytyn, Anna Z, Duimel, Hans Q, van Donselaar, Elly, Riesebosch, Samra, Kuijpers, Helma J H, Schipper, Debby, van de Wetering, Willine J, de Graaf, Miranda, Koopmans, Marion, Cuppen, Edwin, Peters, Peter J, Haagmans, Bart L, Clevers, Hans, Lamers, Mart M, Beumer, Joep, van der Vaart, Jelte, Knoops, Kèvin, Puschhof, Jens, Breugem, Tim I, Ravelli, Raimond B G, Paul van Schayck, J, Mykytyn, Anna Z, Duimel, Hans Q, van Donselaar, Elly, Riesebosch, Samra, Kuijpers, Helma J H, Schipper, Debby, van de Wetering, Willine J, de Graaf, Miranda, Koopmans, Marion, Cuppen, Edwin, Peters, Peter J, Haagmans, Bart L, and Clevers, Hans

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause coronavirus disease 2019 (COVID-19), an influenza-like disease that is primarily thought to infect the lungs with transmission through the respiratory route. However, clinical evidence suggests that the intestine may present another viral target organ. Indeed, the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes. In human small intestinal organoids (hSIOs), enterocytes were readily infected by SARS-CoV and SARS-CoV-2, as demonstrated by confocal and electron microscopy. Enterocytes produced infectious viral particles, whereas messenger RNA expression analysis of hSIOs revealed induction of a generic viral response program. Therefore, the intestinal epithelium supports SARS-CoV-2 replication, and hSIOs serve as an experimental model for coronavirus infection and biology.

Published
2020

33. An Organoid-derived Bronchioalveolar Model for SARS-CoV-2 Infection of Human Alveolar-type II-like Cells

Author

Lamers, Mart M, van der Vaart, Jelte, Knoops, Kèvin, Riesebosch, Samra, Breugem, Tim I, Mykytyn, Anna Z, Beumer, Joep, Schipper, Debby, Bezstarosti, Karel, Koopman, Charlotte D, Groen, Nathalie, Ravelli, Raimond B G, Duimel, Hans Q, Demmers, Jeroen A A, Verjans, Georges M G M, Koopmans, Marion P G, Muraro, Mauro J, Peters, Peter J, Clevers, Hans, Haagmans, Bart L, Lamers, Mart M, van der Vaart, Jelte, Knoops, Kèvin, Riesebosch, Samra, Breugem, Tim I, Mykytyn, Anna Z, Beumer, Joep, Schipper, Debby, Bezstarosti, Karel, Koopman, Charlotte D, Groen, Nathalie, Ravelli, Raimond B G, Duimel, Hans Q, Demmers, Jeroen A A, Verjans, Georges M G M, Koopmans, Marion P G, Muraro, Mauro J, Peters, Peter J, Clevers, Hans, and Haagmans, Bart L

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), may result in acute respiratory distress syndrome (ARDS), multi-organ failure and death. The alveolar epithelium is a major target of the virus, but representative models to study virus host interactions in more detail are currently lacking. Here, we describe a human 2D air-liquid interface culture system which was characterized by confocal-, electron-microscopy and single cell mRNA expression analysis. In this model, alveolar cells, but also basal cells and rare neuroendocrine cells, are grown from 3D self-renewing fetal lung bud tip organoids. These cultures were readily infected by SARS-CoV-2 with mainly surfactant protein C-positive alveolar type II-like cells being targeted. Consequently, significant viral titers were detected and mRNA expression analysis revealed induction of type I/III interferon response program. Treatment of these cultures with a low dose of interferon lambda 1 reduced viral replication. Hence, these cultures represent an experimental model for SARS-CoV-2 infection and can be applied for drug screens.

Published
2020

34. SARS-CoV-2 productively infects human gut enterocytes

Author

CMM, CMM Groep Cuppen, Cancer, CMM Sectie Molecular Cancer Research, Child Health, Regenerative Medicine and Stem Cells, Hubrecht Institute with UMC, Lamers, Mart M, Beumer, Joep, van der Vaart, Jelte, Knoops, Kèvin, Puschhof, Jens, Breugem, Tim I, Ravelli, Raimond B G, Paul van Schayck, J, Mykytyn, Anna Z, Duimel, Hans Q, van Donselaar, Elly, Riesebosch, Samra, Kuijpers, Helma J H, Schippers, Debby, van de Wetering, Willine J, de Graaf, Miranda, Koopmans, Marion, Cuppen, Edwin, Peters, Peter J, Haagmans, Bart L, Clevers, Hans, CMM, CMM Groep Cuppen, Cancer, CMM Sectie Molecular Cancer Research, Child Health, Regenerative Medicine and Stem Cells, Hubrecht Institute with UMC, Lamers, Mart M, Beumer, Joep, van der Vaart, Jelte, Knoops, Kèvin, Puschhof, Jens, Breugem, Tim I, Ravelli, Raimond B G, Paul van Schayck, J, Mykytyn, Anna Z, Duimel, Hans Q, van Donselaar, Elly, Riesebosch, Samra, Kuijpers, Helma J H, Schippers, Debby, van de Wetering, Willine J, de Graaf, Miranda, Koopmans, Marion, Cuppen, Edwin, Peters, Peter J, Haagmans, Bart L, and Clevers, Hans

Published
2020

36. A central cavity within the holo-translocon suggests a mechanism for membrane protein insertion

Author

Botte, Mathieu, primary, Zaccai, Nathan R., additional, Nijeholt, Jelger Lycklama à., additional, Martin, Remy, additional, Knoops, Kèvin, additional, Papai, Gabor, additional, Zou, Juan, additional, Deniaud, Aurélien, additional, Karuppasamy, Manikandan, additional, Jiang, Qiyang, additional, Roy, Abhishek Singha, additional, Schulten, Klaus, additional, Schultz, Patrick, additional, Rappsilber, Juri, additional, Zaccai, Giuseppe, additional, Berger, Imre, additional, Collinson, Ian, additional, and Schaffitzel, Christiane, additional

Published
2016
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38. Structural basis of signal sequence surveillance and selection by the SRP-FtsY complex

Author

Von Loeffelholz, Ottilie, Knoops, Kèvin, Ariosa, Aileen, Zhang, Xin, Karuppasamy, Manikandan, Huard, Karine, Schoehn, Guy, Berger, Imre, Shan, Shu-ou, Schaffitzel, Christiane, Thomas, Frank, China Earthquake Networks Center, China Earthquake Administration (CEA), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), European Molecular Biology Laboratory [Grenoble] (EMBL), Institute of Space Science [Taiwan], National Central University [Taiwan] (NCU), Unit of Virus Host-Cell Interactions, UMR 5233, Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], MESH: Escherichia coli, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], MESH: Escherichia coli Proteins, MESH: Multiprotein Complexes, MESH: Receptors, Cytoplasmic and Nuclear, environment and public health, MESH: Protein Conformation, MESH: Signal Recognition Particle, MESH: Cryoelectron Microscopy, MESH: Serine Endopeptidases, MESH: Protein Sorting Signals, MESH: Bacterial Proteins, MESH: Models, Molecular
Abstract

International audience; Signal-recognition particle (SRP)-dependent targeting of translating ribosomes to membranes is a multistep quality-control process. Ribosomes that are translating weakly hydrophobic signal sequences can be rejected from the targeting reaction even after they are bound to the SRP. Here we show that the early complex, formed by Escherichia coli SRP and its receptor FtsY with ribosomes translating the incorrect cargo EspP, is unstable and rearranges inefficiently into subsequent conformational states, such that FtsY dissociation is favored over successful targeting. The N-terminal extension of EspP is responsible for these defects in the early targeting complex. The cryo-electron microscopy structure of this 'false' early complex with EspP revealed an ordered M domain of SRP protein Ffh making two ribosomal contacts, and the NG domains of Ffh and FtsY forming a distorted, flexible heterodimer. Our results provide a structural basis for SRP-mediated signal-sequence selection during recruitment of the SRP receptor.

Published
2013

43. Integrity of the Early Secretory Pathway Promotes, but Is Not Required for, Severe Acute Respiratory Syndrome Coronavirus RNA Synthesis and Virus-Induced Remodeling of Endoplasmic Reticulum Membranes

Author

Knoops, Kèvin, primary, Swett-Tapia, Cindy, additional, van den Worm, Sjoerd H. E., additional, te Velthuis, Aartjan J. W., additional, Koster, Abraham J., additional, Mommaas, A. Mieke, additional, Snijder, Eric J., additional, and Kikkert, Marjolein, additional

Published
2010
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47. Mycobacteria-host interactions in human bronchiolar airway organoids.

Author

Iakobachvili N, Leon-Icaza SA, Knoops K, Sachs N, Mazères S, Simeone R, Peixoto A, Bernard C, Murris-Espin M, Mazières J, Cam K, Chalut C, Guilhot C, López-Iglesias C, Ravelli RBG, Neyrolles O, Meunier E, Lugo-Villarino G, Clevers H, Cougoule C, and Peters PJ

Subjects
Humans, Macrophages microbiology, Nontuberculous Mycobacteria, Organoids, Mycobacterium abscessus, Mycobacterium tuberculosis, Tuberculosis microbiology
Abstract

Respiratory infections remain a major global health concern. Tuberculosis is one of the top 10 causes of death worldwide, while infections with Non-Tuberculous Mycobacteria are rising globally. Recent advances in human tissue modeling offer a unique opportunity to grow different human "organs" in vitro, including the human airway, that faithfully recapitulates lung architecture and function. Here, we have explored the potential of human airway organoids (AOs) as a novel system in which to assess the very early steps of mycobacterial infection. We reveal that Mycobacterium tuberculosis (Mtb) and Mycobacterium abscessus (Mabs) mainly reside as extracellular bacteria and infect epithelial cells with very low efficiency. While the AO microenvironment was able to control, but not eliminate Mtb, Mabs thrives. We demonstrate that AOs responded to infection by modulating cytokine, antimicrobial peptide, and mucin gene expression. Given the importance of myeloid cells in mycobacterial infection, we co-cultured infected AOs with human monocyte-derived macrophages and found that these cells interact with the organoid epithelium. We conclude that adult stem cell (ASC)-derived AOs can be used to decipher very early events of mycobacteria infection in human settings thus offering new avenues for fundamental and therapeutic research., (© 2021 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

Published
2022
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48. In cellulo serial crystallography of alcohol oxidase crystals inside yeast cells.

Author

Jakobi AJ, Passon DM, Knoops K, Stellato F, Liang M, White TA, Seine T, Messerschmidt M, Chapman HN, and Wilmanns M

Abstract

The possibility of using femtosecond pulses from an X-ray free-electron laser to collect diffraction data from protein crystals formed in their native cellular organelle has been explored. X-ray diffraction of submicrometre-sized alcohol oxidase crystals formed in peroxisomes within cells of genetically modified variants of the methylotrophic yeast Hansenula polymorpha is reported and characterized. The observations are supported by synchrotron radiation-based powder diffraction data and electron microscopy. Based on these findings, the concept of in cellulo serial crystallography on protein targets imported into yeast peroxisomes without the need for protein purification as a requirement for subsequent crystallization is outlined.

Published
2016
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49. Structural basis of signal sequence surveillance and selection by the SRP-FtsY complex.

Author

von Loeffelholz O, Knoops K, Ariosa A, Zhang X, Karuppasamy M, Huard K, Schoehn G, Berger I, Shan SO, and Schaffitzel C

Subjects
Cryoelectron Microscopy, Escherichia coli chemistry, Escherichia coli metabolism, Escherichia coli Proteins chemistry, Escherichia coli Proteins metabolism, Models, Molecular, Multiprotein Complexes chemistry, Protein Conformation, Serine Endopeptidases chemistry, Serine Endopeptidases metabolism, Bacterial Proteins chemistry, Bacterial Proteins metabolism, Protein Sorting Signals, Receptors, Cytoplasmic and Nuclear chemistry, Receptors, Cytoplasmic and Nuclear metabolism, Signal Recognition Particle chemistry, Signal Recognition Particle metabolism
Abstract

Signal-recognition particle (SRP)-dependent targeting of translating ribosomes to membranes is a multistep quality-control process. Ribosomes that are translating weakly hydrophobic signal sequences can be rejected from the targeting reaction even after they are bound to the SRP. Here we show that the early complex, formed by Escherichia coli SRP and its receptor FtsY with ribosomes translating the incorrect cargo EspP, is unstable and rearranges inefficiently into subsequent conformational states, such that FtsY dissociation is favored over successful targeting. The N-terminal extension of EspP is responsible for these defects in the early targeting complex. The cryo-electron microscopy structure of this 'false' early complex with EspP revealed an ordered M domain of SRP protein Ffh making two ribosomal contacts, and the NG domains of Ffh and FtsY forming a distorted, flexible heterodimer. Our results provide a structural basis for SRP-mediated signal-sequence selection during recruitment of the SRP receptor.

Published
2013
Full Text
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