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Induction of cross-reactive antibody responses against the RBD domain of the spike protein of SARS-CoV-2 by commensal microbiota

Justus Ninnemann, Lisa Budzinski, Marina Bondareva, Mario Witkowski, Stefan Angermair, Jakob Kreye, Pawel Durek, S. Momsen Reincke, Elisa Sánchez-Sendin, Selin Yilmaz, Toni Sempert, Gitta Anne Heinz, Caroline Tizian, Martin Raftery, Günther Schönrich, Daria Matyushkina, Ivan V. Smirnov, Vadim M. Govorun, Eva Schrezenmeier, Thomas Dörner, Silvia Zocche, Edoardo Viviano, Katharina Johanna Sehmsdorf, Hyun-Dong Chang, Philipp Enghard, Sascha Treskatsch, Andreas Radbruch, Andreas Diefenbach, View ORCID ProfileHarald Prüss, View ORCID ProfileMir-Farzin Mashreghi, Andrey A. Kruglov
doi: https://doi.org/10.1101/2021.08.08.455272
Justus Ninnemann
1Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association; 10117, Berlin, Germany
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Lisa Budzinski
1Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association; 10117, Berlin, Germany
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Marina Bondareva
1Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association; 10117, Berlin, Germany
2Belozersky Institute of Physico-Chemical Biology and Biological Faculty, M.V. Lomonosov Moscow State University; 119234, Moscow, Russia
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Mario Witkowski
3Berlin Institute of Health (BIH); 10178, Berlin, Germany
4Laboratory of Innate Immunity, Department of Microbiology and Infection Immunology, Charité-Universitätsmedizin Berlin; 12203, Berlin, Germany
5Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, an Institute of the Leibniz Association; 10117, Berlin, Germany
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Stefan Angermair
6Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität and Humboldt Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine, Charité Campus Benjamin Franklin; Berlin, Germany
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Jakob Kreye
3Berlin Institute of Health (BIH); 10178, Berlin, Germany
7German Center for Neurodegenerative Diseases (DZNE) Berlin; 10117, Berlin, Germany
8Helmholtz Innovation Lab BaoBab (Brain Antibody-omics and B-cell Lab); 10117, Berlin, Germany
9Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health; 10117, Berlin, Germany
10Department of Pediatric Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health; 10117, Berlin, Germany
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Pawel Durek
1Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association; 10117, Berlin, Germany
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S. Momsen Reincke
3Berlin Institute of Health (BIH); 10178, Berlin, Germany
7German Center for Neurodegenerative Diseases (DZNE) Berlin; 10117, Berlin, Germany
8Helmholtz Innovation Lab BaoBab (Brain Antibody-omics and B-cell Lab); 10117, Berlin, Germany
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Elisa Sánchez-Sendin
7German Center for Neurodegenerative Diseases (DZNE) Berlin; 10117, Berlin, Germany
8Helmholtz Innovation Lab BaoBab (Brain Antibody-omics and B-cell Lab); 10117, Berlin, Germany
9Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health; 10117, Berlin, Germany
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Selin Yilmaz
1Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association; 10117, Berlin, Germany
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Toni Sempert
1Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association; 10117, Berlin, Germany
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Gitta Anne Heinz
1Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association; 10117, Berlin, Germany
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Caroline Tizian
3Berlin Institute of Health (BIH); 10178, Berlin, Germany
4Laboratory of Innate Immunity, Department of Microbiology and Infection Immunology, Charité-Universitätsmedizin Berlin; 12203, Berlin, Germany
5Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, an Institute of the Leibniz Association; 10117, Berlin, Germany
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Martin Raftery
11Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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Günther Schönrich
11Institute of Virology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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Daria Matyushkina
12Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency; 119435, Moscow, Russia
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Ivan V. Smirnov
13Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences; Moscow 117997, Russia
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Vadim M. Govorun
12Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical and Biological Agency; 119435, Moscow, Russia
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Eva Schrezenmeier
14Department of Nephrology and Intensive Care Medicine,Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; 10117, Berlin, Germany
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Thomas Dörner
1Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association; 10117, Berlin, Germany
15Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Silvia Zocche
16Departments of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité University Medicine; 10117 Berlin, Germany
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Edoardo Viviano
17Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Institute of Physiology, Center for Space Medicine and Extreme Environments Berlin; 10117, Berlin, Germany
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Katharina Johanna Sehmsdorf
14Department of Nephrology and Intensive Care Medicine,Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; 10117, Berlin, Germany
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Hyun-Dong Chang
1Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association; 10117, Berlin, Germany
18Institute of Biotechnology, Technische Universität Berlin; Berlin, Germany
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Philipp Enghard
14Department of Nephrology and Intensive Care Medicine,Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; 10117, Berlin, Germany
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Sascha Treskatsch
6Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität and Humboldt Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine, Charité Campus Benjamin Franklin; Berlin, Germany
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Andreas Radbruch
1Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association; 10117, Berlin, Germany
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Andreas Diefenbach
3Berlin Institute of Health (BIH); 10178, Berlin, Germany
4Laboratory of Innate Immunity, Department of Microbiology and Infection Immunology, Charité-Universitätsmedizin Berlin; 12203, Berlin, Germany
5Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, an Institute of the Leibniz Association; 10117, Berlin, Germany
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Harald Prüss
7German Center for Neurodegenerative Diseases (DZNE) Berlin; 10117, Berlin, Germany
8Helmholtz Innovation Lab BaoBab (Brain Antibody-omics and B-cell Lab); 10117, Berlin, Germany
9Department of Neurology and Experimental Neurology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health; 10117, Berlin, Germany
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  • ORCID record for Harald Prüss
Mir-Farzin Mashreghi
1Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association; 10117, Berlin, Germany
19Department of Pediatric Pulmonology, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin; 10117 Berlin, Germany
20Department BIH Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow-Klinikum; 13353 Berlin, Germany
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Andrey A. Kruglov
1Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association; 10117, Berlin, Germany
2Belozersky Institute of Physico-Chemical Biology and Biological Faculty, M.V. Lomonosov Moscow State University; 119234, Moscow, Russia
21Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences; 119991, Moscow, Russia
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  • For correspondence: kruglov@drfz.de
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Abstract

The commensal microflora is a source for multiple antigens that may induce cross-reactive antibodies against host proteins and pathogens. However, whether commensal bacteria can induce cross-reactive antibodies against SARS-CoV-2 remains unknown. Here we report that several commensal bacteria contribute to the generation of cross-reactive IgA antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein. We identified SARS-CoV-2 unexposed individuals with RBD-binding IgA antibodies at their mucosal surfaces. Conversely, neutralising monoclonal anti-RBD antibodies recognised distinct commensal bacterial species. Some of these bacteria, such as Streptococcus salivarius, induced a cross-reactive anti-RBD antibodies upon supplementation in mice. Conversely, severely ill COVID-19 patients showed reduction of Streptococcus and Veillonella in their oropharynx and feces and a reduction of anti-RBD IgA at mucosal surfaces. Altogether, distinct microbial species of the human microbiota can induce secretory IgA antibodies cross-reactive for the RBD of SARS-CoV-2.

Competing Interest Statement

J.N., L. B., and A.K. have a pending patent application with regard to utilization of commensal bacteria for induction of antiviral immune responses.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Induction of cross-reactive antibody responses against the RBD domain of the spike protein of SARS-CoV-2 by commensal microbiota
Justus Ninnemann, Lisa Budzinski, Marina Bondareva, Mario Witkowski, Stefan Angermair, Jakob Kreye, Pawel Durek, S. Momsen Reincke, Elisa Sánchez-Sendin, Selin Yilmaz, Toni Sempert, Gitta Anne Heinz, Caroline Tizian, Martin Raftery, Günther Schönrich, Daria Matyushkina, Ivan V. Smirnov, Vadim M. Govorun, Eva Schrezenmeier, Thomas Dörner, Silvia Zocche, Edoardo Viviano, Katharina Johanna Sehmsdorf, Hyun-Dong Chang, Philipp Enghard, Sascha Treskatsch, Andreas Radbruch, Andreas Diefenbach, Harald Prüss, Mir-Farzin Mashreghi, Andrey A. Kruglov
bioRxiv 2021.08.08.455272; doi: https://doi.org/10.1101/2021.08.08.455272
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Induction of cross-reactive antibody responses against the RBD domain of the spike protein of SARS-CoV-2 by commensal microbiota
Justus Ninnemann, Lisa Budzinski, Marina Bondareva, Mario Witkowski, Stefan Angermair, Jakob Kreye, Pawel Durek, S. Momsen Reincke, Elisa Sánchez-Sendin, Selin Yilmaz, Toni Sempert, Gitta Anne Heinz, Caroline Tizian, Martin Raftery, Günther Schönrich, Daria Matyushkina, Ivan V. Smirnov, Vadim M. Govorun, Eva Schrezenmeier, Thomas Dörner, Silvia Zocche, Edoardo Viviano, Katharina Johanna Sehmsdorf, Hyun-Dong Chang, Philipp Enghard, Sascha Treskatsch, Andreas Radbruch, Andreas Diefenbach, Harald Prüss, Mir-Farzin Mashreghi, Andrey A. Kruglov
bioRxiv 2021.08.08.455272; doi: https://doi.org/10.1101/2021.08.08.455272

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