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Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system

Ludovico Cantuti-Castelvetri, Ravi Ojha, Liliana D. Pedro, Minou Djannatian, Jonas Franz, Suvi Kuivanen, Katri Kallio, Tuğberk Kaya, Maria Anastasina, Teemu Smura, Lev Levanov, Leonora Szirovicza, Allan Tobi, Hannimari Kallio-Kokko, Pamela Österlund, Merja Joensuu, Frédéric A. Meunier, Sarah Butcher, Martin Sebastian Winkler, Brit Mollenhauer, Ari Helenius, Ozgun Gokce, Tambet Teesalu, Jussi Hepojoki, Olli Vapalahti, Christine Stadelmann, Giuseppe Balistreri, Mikael Simons
doi: https://doi.org/10.1101/2020.06.07.137802
Ludovico Cantuti-Castelvetri
1Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
2German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
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Ravi Ojha
3Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
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Liliana D. Pedro
1Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
2German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
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Minou Djannatian
1Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
2German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
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Jonas Franz
4Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
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Suvi Kuivanen
5University of Helsinki, Medicum, Department of Virology, Helsinki, Finland
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Katri Kallio
3Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
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Tuğberk Kaya
1Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
2German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
6Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
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Maria Anastasina
3Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
7Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Finland
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Teemu Smura
5University of Helsinki, Medicum, Department of Virology, Helsinki, Finland
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Lev Levanov
5University of Helsinki, Medicum, Department of Virology, Helsinki, Finland
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Leonora Szirovicza
5University of Helsinki, Medicum, Department of Virology, Helsinki, Finland
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Allan Tobi
8Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
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Hannimari Kallio-Kokko
9University of Helsinki and Helsinki University Hospital, Department of Virology, Helsinki, Finland
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Pamela Österlund
10Department of Health Security, Finnish Institute for Health and Welfare (THL), Helsinki, Finland
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Merja Joensuu
11Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
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Frédéric A. Meunier
11Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
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Sarah Butcher
3Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
7Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Finland
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Martin Sebastian Winkler
12Department of Anesthesiology and Intensive Care Medicine, University Medical Center Göttingen, Göttingen, Germany
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Brit Mollenhauer
13Department of Neurology, University Medical Center Göttingen, Göttingen, Germany & Paracelsus-Elena-Klinik Kassel, Kassel, Germany
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Ari Helenius
14Institute of Biochemistry, ETH Zürich, Zürich, Switzerland
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Ozgun Gokce
6Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
19Munich Cluster of Systems Neurology (SyNergy), Munich, Germany
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Tambet Teesalu
3Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
15Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
16Center for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California, USA
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Jussi Hepojoki
5University of Helsinki, Medicum, Department of Virology, Helsinki, Finland
17Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
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Olli Vapalahti
5University of Helsinki, Medicum, Department of Virology, Helsinki, Finland
9University of Helsinki and Helsinki University Hospital, Department of Virology, Helsinki, Finland
18Dept of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
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Christine Stadelmann
4Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
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Giuseppe Balistreri
3Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland
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  • For correspondence: giuseppe.balistreri@helsinki.fi mikael.simons@dzne.de
Mikael Simons
1Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
2German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
19Munich Cluster of Systems Neurology (SyNergy), Munich, Germany
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  • For correspondence: giuseppe.balistreri@helsinki.fi mikael.simons@dzne.de
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SUMMARY

The causative agent of the current pandemic and coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. Understanding how SARS-CoV-2 enters and spreads within human organs is crucial for developing strategies to prevent viral dissemination. For many viruses, tissue tropism is determined by the availability of virus receptors on the surface of host cells2. Both SARS-CoV and SARS-CoV-2 use angiotensin-converting enzyme 2 (ACE2) as a host receptor, yet, their tropisms differ3-5. Here, we found that the cellular receptor neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, which was inhibited by a monoclonal blocking antibody against the extracellular b1b2 domain of NRP1. NRP1 is abundantly expressed in the respiratory and olfactory epithelium, with highest expression in endothelial cells and in the epithelial cells facing the nasal cavity. Neuropathological analysis of human COVID-19 autopsies revealed SARS-CoV-2 infected NRP1-positive cells in the olfactory epithelium and bulb. In the olfactory bulb infection was detected particularly within NRP1-positive endothelial cells of small capillaries and medium-sized vessels. Studies in mice demonstrated, after intranasal application, NRP1-mediated transport of virus-sized particles into the central nervous system. Thus, NRP1 could explain the enhanced tropism and spreading of SARS-CoV-2.

Competing Interest Statement

The authors have declared no competing interest.

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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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Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system
Ludovico Cantuti-Castelvetri, Ravi Ojha, Liliana D. Pedro, Minou Djannatian, Jonas Franz, Suvi Kuivanen, Katri Kallio, Tuğberk Kaya, Maria Anastasina, Teemu Smura, Lev Levanov, Leonora Szirovicza, Allan Tobi, Hannimari Kallio-Kokko, Pamela Österlund, Merja Joensuu, Frédéric A. Meunier, Sarah Butcher, Martin Sebastian Winkler, Brit Mollenhauer, Ari Helenius, Ozgun Gokce, Tambet Teesalu, Jussi Hepojoki, Olli Vapalahti, Christine Stadelmann, Giuseppe Balistreri, Mikael Simons
bioRxiv 2020.06.07.137802; doi: https://doi.org/10.1101/2020.06.07.137802
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Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system
Ludovico Cantuti-Castelvetri, Ravi Ojha, Liliana D. Pedro, Minou Djannatian, Jonas Franz, Suvi Kuivanen, Katri Kallio, Tuğberk Kaya, Maria Anastasina, Teemu Smura, Lev Levanov, Leonora Szirovicza, Allan Tobi, Hannimari Kallio-Kokko, Pamela Österlund, Merja Joensuu, Frédéric A. Meunier, Sarah Butcher, Martin Sebastian Winkler, Brit Mollenhauer, Ari Helenius, Ozgun Gokce, Tambet Teesalu, Jussi Hepojoki, Olli Vapalahti, Christine Stadelmann, Giuseppe Balistreri, Mikael Simons
bioRxiv 2020.06.07.137802; doi: https://doi.org/10.1101/2020.06.07.137802

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