Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19

Ronja Mothes, Anna Pascual-Reguant, Ralf Koehler, Juliane Liebeskind, Alina Liebheit, Sandy Bauherr, Lars Philipsen, Carsten Dittmayer, Michael Laue, Regina Manitius, Sefer Elezkurtaj, Pawel Durek, Frederik Heinrich, Gitta A. Heinz, Gabriela M. Guerra, Benedikt Obermayer, Jenny Meinhardt, Jana Ihlow, Josefine Radke, Frank L. Heppner, Philipp Enghard, Helena Stockmann, Tom Aschman, Julia Schneider, Victor M. Corman, Leif E. Sander, Mir-Farzin Mashreghi, Thomas Conrad, Andreas C. Hocke, Raluca A. Niesner, Helena Radbruch and Anja E. Hauser ()
Additional contact information
Ronja Mothes: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Anna Pascual-Reguant: Immune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
Ralf Koehler: Immune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
Juliane Liebeskind: Immune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
Alina Liebheit: Immune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
Sandy Bauherr: Immune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
Lars Philipsen: Otto-von-Guericke University Magdeburg
Carsten Dittmayer: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Michael Laue: Robert Koch Institute
Regina Manitius: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Sefer Elezkurtaj: Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Pawel Durek: Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
Frederik Heinrich: Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
Gitta A. Heinz: Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
Gabriela M. Guerra: Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
Benedikt Obermayer: Berlin Institute of Health at Charité-Universitätsmedizin Berlin
Jenny Meinhardt: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Jana Ihlow: Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Josefine Radke: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Frank L. Heppner: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Philipp Enghard: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Helena Stockmann: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin
Tom Aschman: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Julia Schneider: Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin and German Centre for Infection Research
Victor M. Corman: Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin and German Centre for Infection Research
Leif E. Sander: Berlin Institute of Health (BIH)
Mir-Farzin Mashreghi: Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute
Thomas Conrad: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Andreas C. Hocke: Charité-Universitätsmedizin Berlin and German Center for Lung Research (DZL)
Raluca A. Niesner: Freie Universität Berlin
Helena Radbruch: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Anja E. Hauser: Immune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), a Leibniz Institute

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Prolonged lung pathology has been associated with COVID-19, yet the cellular and molecular mechanisms behind this chronic inflammatory disease are poorly understood. In this study, we combine advanced imaging and spatial transcriptomics to shed light on the local immune response in severe COVID-19. We show that activated adventitial niches are crucial microenvironments contributing to the orchestration of prolonged lung immunopathology. Up-regulation of the chemokines CCL21 and CCL18 associates to endothelial-to-mesenchymal transition and tissue fibrosis within these niches. CCL21 over-expression additionally links to the local accumulation of T cells expressing the cognate receptor CCR7. These T cells are imprinted with an exhausted phenotype and form lymphoid aggregates that can organize in ectopic lymphoid structures. Our work proposes immune-stromal interaction mechanisms promoting a self-sustained and non-resolving local immune response that extends beyond active viral infection and perpetuates tissue remodeling.

Date: 2023
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DOI: 10.1038/s41467-023-36333-2

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