Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages.


Journal

Cell research
ISSN: 1748-7838
Titre abrégé: Cell Res
Pays: England
ID NLM: 9425763

Informations de publication

Date de publication:
03 2021
Historique:
received: 02 07 2020
accepted: 20 11 2020
pubmed: 22 1 2021
medline: 16 3 2021
entrez: 21 1 2021
Statut: ppublish

Résumé

How the innate and adaptive host immune system miscommunicate to worsen COVID-19 immunopathology has not been fully elucidated. Here, we perform single-cell deep-immune profiling of bronchoalveolar lavage (BAL) samples from 5 patients with mild and 26 with critical COVID-19 in comparison to BALs from non-COVID-19 pneumonia and normal lung. We use pseudotime inference to build T-cell and monocyte-to-macrophage trajectories and model gene expression changes along them. In mild COVID-19, CD8

Identifiants

pubmed: 33473155
doi: 10.1038/s41422-020-00455-9
pii: 10.1038/s41422-020-00455-9
pmc: PMC8027624
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

272-290

Subventions

Organisme : Vlaams Instituut voor Biotechnologie (Flanders Institute for Biotechnology)
ID : VR 2016 2312 Doc.1521/4
Organisme : Stichting Tegen Kanker (Belgian Foundation Against Cancer)
ID : 1833317N
Organisme : Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)
ID : 1S66020N
Organisme : Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)
ID : 11E9819N
Organisme : Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)
ID : 1833317N

Investigateurs

Maria Bosisio (M)
Michael Casaer (M)
Frederik De Smet (F)
Paul De Munter (P)
Stephanie Humblet-Baron (S)
Adrian Liston (A)
Natalie Lorent (N)
Kim Martinod (K)
Paul Proost (P)
Jeroen Raes (J)
Karin Thevissen (K)
Robin Vos (R)
Birgit Weynand (B)
Carine Wouters (C)

Références

World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard. Covid-19 Dashboard 1–1 (2020).
Fu, L. et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review and meta-analysis. J. Infect. 80, 656–665 (2020).
pubmed: 32283155 pmcid: 7151416 doi: 10.1016/j.jinf.2020.03.041
Chen, G. et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Investig. 130, 2620–2629 (2020).
pubmed: 32217835 pmcid: 7190990 doi: 10.1172/JCI137244
Liu, K. et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin. Med. J. (Engl). 133, 1025–1031 (2020).
pubmed: 32044814 pmcid: 7147277 doi: 10.1097/CM9.0000000000000744
Wen, W. et al. Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing. Cell Discov. 6, 31, https://doi.org/10.1038/s41421-020-0168-9 (2020).
doi: 10.1038/s41421-020-0168-9 pubmed: 32377375 pmcid: 7197635
Wilk, A. J. et al. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat. Med. 26, 1070–1076 (2020).
pubmed: 32514174 pmcid: 7382903 doi: 10.1038/s41591-020-0944-y
Vanderbeke, L. et al. Monocyte-Driven Atypical Cytokine Storm and Aberrant Neutrophil Activation as Key Mediators of COVID19 Disease Severity. SSRN (2020). https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3646561 .
Schulte-Schrepping, J. et al. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell 182, 1419–1440 (2020).
pubmed: 32810438 pmcid: 7405822 doi: 10.1016/j.cell.2020.08.001
Silvin, A. et al. Elevated calprotectin and abnormal myeloid cell subsets discriminate severe from mild COVID-19. Cell 182, 1401–1418 (2020).
pubmed: 32810439 pmcid: 7405878 doi: 10.1016/j.cell.2020.08.002
Zhang, J. Y. et al. Single-cell landscape of immunological responses in patients with COVID-19. Nat. Immunol. 21, 1107–1118 (2020).
pubmed: 32788748 doi: 10.1038/s41590-020-0762-x
Lee, J. S. et al. Immunophenotyping of COVID-19 and influenza highlights the role of type i interferons in development of severe COVID-19. Sci. Immunol. 5, eabd1554 (2020).
pubmed: 32651212 pmcid: 7402635 doi: 10.1126/sciimmunol.abd1554
Cao, Y. et al. Potent Neutralizing Antibodies against SARS-CoV-2 Identified by High-Throughput Single-Cell Sequencing of Convalescent Patients’ B Cells. Cell 182, 73–84 (2020).
pubmed: 32425270 pmcid: 7231725 doi: 10.1016/j.cell.2020.05.025
Zhang, F. et al. Adaptive immune responses to SARS-CoV-2 infection in severe versus mild individuals. Signal Transduct. Target. Ther. 5, 156 (2020).
pubmed: 32796814 pmcid: 7426596 doi: 10.1038/s41392-020-00263-y
Liao, M. et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat. Med. 26, 842–844 (2020).
pubmed: 32398875 doi: 10.1038/s41591-020-0901-9
Bost, P. et al. Host-viral infection maps reveal signatures of severe COVID-19 patients. Cell 181, 1475–1488 (2020).
pubmed: 32479746 pmcid: 7205692 doi: 10.1016/j.cell.2020.05.006
Chua, R. L. et al. COVID-19 severity correlates with airway epithelium–immune cell interactions identified by single-cell analysis. Nat. Biotechnol. 38, 970–979 (2020).
pubmed: 32591762 doi: 10.1038/s41587-020-0602-4
Lambrechts, D. et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 24, 1277–1289 (2018).
pubmed: 29988129 doi: 10.1038/s41591-018-0096-5
Reyfman, P. A. et al. Single-cell transcriptomic analysis of human lung provides insights into the pathobiology of pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 9, 1517–1536 (2019).
doi: 10.1164/rccm.201712-2410OC
Qian, J. et al. A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling. Cell Res. 30, 745–762 (2020).
pubmed: 32561858 pmcid: 7608385 doi: 10.1038/s41422-020-0355-0
Garg, A. D. & Agostinis, P. Cell death and immunity in cancer: from danger signals to mimicry of pathogen defense responses. Immunol. Rev. 280, 126–148 (2017).
pubmed: 29027218 doi: 10.1111/imr.12574
Van Driel, B. J., Liao, G., Engel, P. & Terhorst, C. Responses to microbial challenges by SLAMF receptors. Front. Immunol. 7, 1–14 (2016).
Wherry, E. J. et al. Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection. Immunity 27, 670–684 (2007).
pubmed: 17950003 doi: 10.1016/j.immuni.2007.09.006
Wang, W. H. et al. The role of galectins in virus infection - a systemic literature review. J. Microbiol. Immunol. Infect. 53, 925–935 (2019).
pubmed: 31630962 doi: 10.1016/j.jmii.2019.09.005
Liu, W. et al. Tim-4 in Health and Disease: friend or Foe? Front. Immunol. 11, 1–10 (2020).
Ohkura, N. & Sakaguchi, S. Transcriptional and epigenetic basis of Treg cell development and function: its genetic anomalies or variations in autoimmune diseases. Cell Res. 30, 465–474 (2020).
pubmed: 32367041 pmcid: 7264322 doi: 10.1038/s41422-020-0324-7
Serroukh, Y. et al. The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes. Elife 7, 1–27 (2018).
doi: 10.7554/eLife.30496
Chechlinska, M. et al. Molecular signature of cell cycle exit induced in human T lymphoblasts by IL-2 withdrawal. BMC Genom. 10, 261 (2009).
doi: 10.1186/1471-2164-10-261
Miyazaki, Y., Chen, L. C., Chu, B. W., Swigut, T. & Wandless, T. J. Distinct transcriptional responses elicited by unfolded nuclear or cytoplasmic protein in mammalian cells. Elife 4, 1–24 (2015).
doi: 10.7554/eLife.07687
Ma, W. T., Yao, X. T., Peng, Q. & Chen, D. K. The protective and pathogenic roles of IL-17 in viral infections: Friend or foe? Open Biol. 9, 190109 (2019).
pubmed: 31337278 pmcid: 6685926 doi: 10.1098/rsob.190109
Cecchinato, V. et al. Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques. Mucosal Immunol. 1, 279–288 (2008).
pubmed: 19079189 pmcid: 2997489 doi: 10.1038/mi.2008.14
Cohen, M. et al. Lung Single-Cell Signaling Interaction Map Reveals Basophil Role in Macrophage Imprinting. Cell 175, 1031–1044 (2018).
pubmed: 30318149 doi: 10.1016/j.cell.2018.09.009
Liu, H., Shi, B., Huang, C. C., Eksarko, P. & Pope, R. M. Transcriptional diversity during monocyte to macrophage differentiation. Immunol. Lett. 117, 70–80 (2008).
pubmed: 18276018 pmcid: 2838727 doi: 10.1016/j.imlet.2007.12.012
Willingham, S. B. et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc. Natl. Acad. Sci. USA. 109, 6662–6667 (2012).
pubmed: 22451913 pmcid: 3340046 doi: 10.1073/pnas.1121623109
Garg, A. D., Romano, E., Rufo, N. & Agostinis, P. Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation. Cell Death Differ 23, 938–951 (2016).
pubmed: 26891691 pmcid: 4987738 doi: 10.1038/cdd.2016.5
Cauwels, A., Rogge, E., Vandendriessche, B., Shiva, S. & Brouckaert, P. Extracellular ATP drives systemic inflammation, tissue damage and mortality. Cell Death Dis. 5, 1–7 (2014).
doi: 10.1038/cddis.2014.70
Krysko, D. V. et al. Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol. 32, 157–164 (2011).
pubmed: 21334975 doi: 10.1016/j.it.2011.01.005
Riteau, N. et al. Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis. Am. J. Respir. Crit. Care Med. 182, 774–783 (2010).
pubmed: 20522787 doi: 10.1164/rccm.201003-0359OC
Gavin, C. et al. The Complement System Is Essential for the Phagocytosis of Mesenchymal Stromal Cells by Monocytes. Front. Immunol. 10, 2249 (2019).
pubmed: 31616424 pmcid: 6763726 doi: 10.3389/fimmu.2019.02249
Tippett, E., Cameron, P. U., Marsh, M. & Crowe, S. M. Characterization of tetraspanins CD9, CD53, CD63, and CD81 in monocytes and macrophages in HIV-1infection. J. Leukoc. Biol. 93, 913–920 (2013).
pubmed: 23570947 doi: 10.1189/jlb.0812391
Lévesque, S. A., Kukulski, F., Enjyoji, K., Robson, S. C. & Sévigny, J. NTPDase1 governs P2X7-dependent functions in murine macrophages. Eur. J. Immunol. 40, 1473–1485 (2010).
pubmed: 20201036 pmcid: 3045779 doi: 10.1002/eji.200939741
Travaglini, K. et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature 587, 619–625 (2020).
pubmed: 33208946 pmcid: 7704697 doi: 10.1038/s41586-020-2922-4
Garg, A. D. et al. Pathogen response-like recruitment and activation of neutrophils by sterile immunogenic dying cells drives neutrophil-mediated residual cell killing. Cell Death Differ. 24, 832–843 (2017).
pubmed: 28234357 pmcid: 5423108 doi: 10.1038/cdd.2017.15
Hiepe, F. et al. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat. Rev. Rheumatol. 7, 170–178 (2011).
pubmed: 21283146 doi: 10.1038/nrrheum.2011.1
Nutt, S. L., Hodgkin, P. D., Tarlinton, D. M. & Corcoran, L. M. The generation of antibody-secreting plasma cells. Nat. Rev. Immunol. 15, 160–171 (2015).
pubmed: 25698678 doi: 10.1038/nri3795
Deprez, M. et al. A Single-cell Atlas of the Human Healthy Airways. Am. J. Respir. Crit. Care Med. 202, 1636–1645 (2020).
pubmed: 32726565 doi: 10.1164/rccm.201911-2199OC
García-Sastre, A. Ten Strategies of Interferon Evasion by Viruses. Cell Host Microbe. 22, 176–184 (2017).
pubmed: 28799903 pmcid: 5576560 doi: 10.1016/j.chom.2017.07.012
Laghlali, G., Lawlor, K. E. & Tate, M. D. Die another way: interplay between influenza A virus, inflammation and cell death. Viruses 12, 1–23 (2020).
doi: 10.3390/v12040401
Zheng, S. et al. Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study. BMJ 369, 1–8 (2020).
Galani, I. E. & Andreakos, E. Neutrophils in viral infections: current concepts and caveats. J. Leukoc. Biol. 98, 557–564 (2015).
pubmed: 26160849 doi: 10.1189/jlb.4VMR1114-555R
Dick, J. et al. C5a receptor 1 promotes autoimmunity, neutrophil dysfunction and injury in experimental anti-myeloperoxidase glomerulonephritis. Kidney Int. 93, 615–625 (2018).
pubmed: 29241626 doi: 10.1016/j.kint.2017.09.018
Leitner, J., Herndler-Brandstetter, D., Zlabinger, G. J., Grubeck-Loebenstein, B. & Steinberger, P. CD58/CD2 Is the Primary Costimulatory Pathway in Human CD28
pubmed: 26041540 doi: 10.4049/jimmunol.1401917
Kaiser, B. K. et al. Interactions between NKG2x Immunoreceptors and HLA-E Ligands Display Overlapping Affinities and Thermodynamics. J. Immunol. 174, 2878–2884 (2005).
pubmed: 15728498 doi: 10.4049/jimmunol.174.5.2878
Schett, G. & Neurath, M. F. Resolution of chronic inflammatory disease: universal and tissue-specific concepts. Nat. Commun. 9, 3261 (2018).
pubmed: 30111884 pmcid: 6093916 doi: 10.1038/s41467-018-05800-6
Arandjelovic, S. & Ravichandran, K. S. Phagocytosis of apoptotic cells in homeostasis. Nat. Immunol. 16, 907–917 (2015).
pubmed: 26287597 pmcid: 4826466 doi: 10.1038/ni.3253
Bratton, D. L. & Henson, P. M. Neutrophil clearance: when the party is over, clean-up begins. Trends Immunol. 32, 350–357 (2011).
pubmed: 21782511 pmcid: 3151332 doi: 10.1016/j.it.2011.04.009
Hochreiter-hufford, A. & Ravichandran, K. S. Clearing the Dead: apoptotic Cell Sensing. Cold Spring Harb. Perspect. Biol. 5, a008748 (2013).
pubmed: 23284042 pmcid: 3579390 doi: 10.1101/cshperspect.a008748
Merad, M. & Martin, J. C. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat. Rev. Immunol. 20, 355–362 (2020).
pubmed: 32376901 pmcid: 7201395 doi: 10.1038/s41577-020-0331-4
Jose, R. J. & Manuel, A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir. Med. 8, e46–e47 (2020).
pubmed: 32353251 doi: 10.1016/S2213-2600(20)30216-2
McGonagle, D., O’Donnell, J. S., Sharif, K., Emery, P. & Bridgewood, C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatol. 2019, 1–9 (2020).
The RECOVERY Collaborative Group. et al. Dexamethasone in Hospitalized Patients with Covid-19 – Preliminary Report. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2021436 (2020).
doi: 10.1056/NEJMoa2021436 pmcid: 7556338
Wan, T., Zhao, Y., Fan, F., Hu, R. & Jin, X. Dexamethasone inhibits S. aureus-induced neutrophil extracellular pathogen-killing mechanism, possibly through toll-like receptor regulation. Front. Immunol. 8, 60, https://doi.org/10.3389/fimmu.2017.00060 (2017).
doi: 10.3389/fimmu.2017.00060 pubmed: 28232829 pmcid: 5299007
Cain, D. W. & Cidlowski, J. A. Immune regulation by glucocorticoids. Nat. Rev. Immunol. 17, 233–247 (2017).
pubmed: 28192415 doi: 10.1038/nri.2017.1
Gutsol, A. A., Sokhonevich, N. A., Seledtsov, V. I. & Litvinova, L. S. Dexamethasone effects on activation and proliferation of immune memory T cells. Bull. Exp. Biol. Med. 155, 474–476 (2013).
pubmed: 24143372 doi: 10.1007/s10517-013-2182-5
Barnes, B. J. et al. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J. Exp. Med. 217, 1–7 (2020).
doi: 10.1084/jem.20200652
Grein, J. et al. Compassionate use of remdesivir for patients with severe Covid-19. N. Engl. J. Med. 382, 2327–2336 (2020).
pubmed: 32275812 doi: 10.1056/NEJMoa2007016
Geleris, J. et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N. Engl. J. Med. 382, 2411–2418 (2020).
pubmed: 32379955 doi: 10.1056/NEJMoa2012410
Horby, P. et al. Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial. medRxiv 2020.07.15.20151852 (2020).
Stuart, T. et al. Comprehensive Integration of Single-Cell Data. Cell 177, 1888–1902 (2019).
pubmed: 31178118 pmcid: 6687398 doi: 10.1016/j.cell.2019.05.031
Van Den Brink, S. C. et al. Single-cell sequencing reveals dissociation-induced gene expression in tissue subpopulations. Nat. Methods 14, 935–936 (2017).
pubmed: 28960196 doi: 10.1038/nmeth.4437
Buffa, F. M., Harris, A. L., West, C. M. & Miller, C. J. Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene. Br. J. Cancer 102, 428–435 (2010).
pubmed: 20087356 pmcid: 2816644 doi: 10.1038/sj.bjc.6605450
McGinnis, C. S., Murrow, L. M. & Gartner, Z. J. DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors. Cell Syst. 8, 329–337.e4 (2019).
pubmed: 30954475 pmcid: 6853612 doi: 10.1016/j.cels.2019.03.003
Wolock, S. L., Lopez, R. & Klein, A. M. Scrublet: computational Identification of Cell Doublets in Single-Cell Transcriptomic Data. Cell Syst. 8, 281–291.e9 (2019).
pubmed: 30954476 pmcid: 6625319 doi: 10.1016/j.cels.2018.11.005
Street, K. et al. Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genom. 19, 477 (2018).
doi: 10.1186/s12864-018-4772-0
Zhu, W. et al. A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4+ T cell receptor repertoire clonality. Oncoimmunology 4, e1051922 (2015).
pubmed: 26587322 pmcid: 4635865 doi: 10.1080/2162402X.2015.1051922
Robinson, J. P. W. et al. The limitations of diversity metrics in directing global marine conservation. Mar. Policy 48, 123–125 (2014).
doi: 10.1016/j.marpol.2014.03.012
Aibar, S. et al. SCENIC: single-cell regulatory network inference and clustering. Nat. Methods 14, 1083–1086 (2017).
pubmed: 28991892 pmcid: 5937676 doi: 10.1038/nmeth.4463
Van den Berge, K. et al. Trajectory-based differential expression analysis for single-cell sequencing data. Nat. Commun. 11, 1–13 (2020).
Federico, A. & Monti, S. HypeR: an R package for geneset enrichment workflows. Bioinformatics 36, 1307–1308 (2020).
pubmed: 31498385 doi: 10.1093/bioinformatics/btz700
Kim, D. et al. The Architecture of SARS-CoV-2 Transcriptome. Cell 181, 914–921 (2020).
pubmed: 32330414 pmcid: 7179501 doi: 10.1016/j.cell.2020.04.011
Efremova, M., Vento-Tormo, M., Teichmann, S. A. & Vento-Tormo, R. CellPhoneDB: inferring cell–cell communication from combined expression of multi-subunit ligand–receptor complexes. Nat. Protoc. 15, 1484–1506 (2020).
pubmed: 32103204 doi: 10.1038/s41596-020-0292-x
Gattinoni, L., Speiser, D. E., Lichterfeld, M. & Bonini, C. T memory stem cells in health and disease. Nat. Med. 23, 18–27 (2017).
pubmed: 28060797 pmcid: 6354775 doi: 10.1038/nm.4241

Auteurs

Els Wauters (E)

Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
Department of Pneumology, University Hospitals Leuven, Leuven, Belgium.

Pierre Van Mol (P)

Department of Pneumology, University Hospitals Leuven, Leuven, Belgium.
Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
VIB Center for Cancer Biology, VIB, Leuven, Belgium.

Abhishek Dinkarnath Garg (AD)

Laboratory for Cell Stress & Immunity (CSI), Department of Cellular and Molecular Medicine (CMM), KU Leuven, Leuven, Belgium.

Sander Jansen (S)

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.

Yannick Van Herck (Y)

Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.

Lore Vanderbeke (L)

Laboratory of Clinical Bacteriology and Mycology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

Ayse Bassez (A)

Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
VIB Center for Cancer Biology, VIB, Leuven, Belgium.

Bram Boeckx (B)

Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
VIB Center for Cancer Biology, VIB, Leuven, Belgium.

Bert Malengier-Devlies (B)

Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.

Anna Timmerman (A)

Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
VIB Center for Cancer Biology, VIB, Leuven, Belgium.

Thomas Van Brussel (T)

Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
VIB Center for Cancer Biology, VIB, Leuven, Belgium.

Tina Van Buyten (T)

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.

Rogier Schepers (R)

Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
VIB Center for Cancer Biology, VIB, Leuven, Belgium.

Elisabeth Heylen (E)

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.

Dieter Dauwe (D)

Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.

Christophe Dooms (C)

Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
Department of Pneumology, University Hospitals Leuven, Leuven, Belgium.

Jan Gunst (J)

Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.

Greet Hermans (G)

Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.

Philippe Meersseman (P)

Laboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

Dries Testelmans (D)

Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
Department of Pneumology, University Hospitals Leuven, Leuven, Belgium.

Jonas Yserbyt (J)

Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
Department of Pneumology, University Hospitals Leuven, Leuven, Belgium.

Sabine Tejpar (S)

Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.

Walter De Wever (W)

Department of Imaging & Pathology, KU Leuven, Leuven, Belgium.

Patrick Matthys (P)

Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.

Johan Neyts (J)

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.

Joost Wauters (J)

Laboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.

Junbin Qian (J)

Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China. dr_qian@zju.edu.cn.

Diether Lambrechts (D)

Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. Diether.Lambrechts@kuleuven.vib.be.
VIB Center for Cancer Biology, VIB, Leuven, Belgium. Diether.Lambrechts@kuleuven.vib.be.

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