Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity

Ludovico Cantuti-Castelvetri; Ravi Ojha; Liliana D Pedro; Minou Djannatian; Jonas Franz; Suvi Kuivanen; Franziska van der Meer; 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 J Butcher; Martin Sebastian Winkler; Brit Mollenhauer; Ari Helenius; Ozgun Gokce; Tambet Teesalu; Jussi Hepojoki; Olli Vapalahti; Christine Stadelmann; Giuseppe Balistreri; Mikael Simons

doi:10.1126/science.abd2985

Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity

Science. 2020 Nov 13;370(6518):856-860. doi: 10.1126/science.abd2985. Epub 2020 Oct 20.

Authors

Ludovico Cantuti-Castelvetri^#^{1

2}, Ravi Ojha^#³, Liliana D Pedro^#^{1

2}, Minou Djannatian^#^{1

2}, Jonas Franz^#^{4

5

6}, Suvi Kuivanen^#⁷, Franziska van der Meer⁴, Katri Kallio³, Tuğberk Kaya^{1

2

8}, Maria Anastasina^{3

9}, Teemu Smura⁷, Lev Levanov⁷, Leonora Szirovicza⁷, Allan Tobi¹⁰, Hannimari Kallio-Kokko¹¹, Pamela Österlund¹², Merja Joensuu¹³, Frédéric A Meunier¹³, Sarah J Butcher^{3

9}, Martin Sebastian Winkler¹⁴, Brit Mollenhauer^{15

16}, Ari Helenius¹⁷, Ozgun Gokce⁸, Tambet Teesalu^{3

18

19}, Jussi Hepojoki^{5

20}, Olli Vapalahti^{7

11

21}, Christine Stadelmann⁴, Giuseppe Balistreri^{22

23}, Mikael Simons^{24

2

25}

Affiliations

¹ Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany.
² German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
³ Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland.
⁴ Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.
⁵ Campus Institute for Dynamics of Biological Networks, University of Göttingen, Göttingen, Germany.
⁶ Max Planck Institute for Experimental Medicine, Göttingen, Germany.
⁷ Department of Virology, Medicum, University of Helsinki, Helsinki, Finland.
⁸ Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
⁹ Helsinki Institute of Life Sciences-Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
¹⁰ Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
¹¹ Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
¹² Department of Health Security, Finnish Institute for Health and Welfare (THL), Helsinki, Finland.
¹³ Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
¹⁴ Department of Anesthesiology and Intensive Care Medicine, University Medical Center Göttingen, Göttingen, Germany.
¹⁵ Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
¹⁶ Paracelsus-Elena-Klinik Kassel, Kassel, Germany.
¹⁷ Institute of Biochemistry, ETH Zürich, Zürich, Switzerland.
¹⁸ Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
¹⁹ Center for Nanomedicine and Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA.
²⁰ Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland.
²¹ Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.
²² Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland. [email protected] [email protected].
²³ The Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
²⁴ Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany. [email protected] [email protected].
²⁵ Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.

^# Contributed equally.

Abstract

The causative agent of coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. In this study, we found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1. A SARS-CoV-2 mutant with an altered furin cleavage site did not depend on NRP1 for infectivity. Pathological analysis of olfactory epithelium obtained from human COVID-19 autopsies revealed that SARS-CoV-2 infected NRP1-positive cells facing the nasal cavity. Our data provide insight into SARS-CoV-2 cell infectivity and define a potential target for antiviral intervention.

Publication types

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

MeSH terms

Angiotensin-Converting Enzyme 2
Animals
Antibodies, Monoclonal / immunology
Betacoronavirus / genetics
Betacoronavirus / physiology*
COVID-19
Caco-2 Cells
Coronavirus Infections / virology*
Female
HEK293 Cells
Host Microbial Interactions
Humans
Lung / metabolism
Male
Metal Nanoparticles
Mice
Mice, Inbred C57BL
Mutation
Neuropilin-1 / chemistry
Neuropilin-1 / genetics
Neuropilin-1 / immunology
Neuropilin-1 / metabolism*
Neuropilin-2 / metabolism
Olfactory Mucosa / metabolism
Olfactory Mucosa / virology
Pandemics
Peptide Fragments / metabolism
Peptidyl-Dipeptidase A / genetics
Peptidyl-Dipeptidase A / metabolism
Pneumonia, Viral / virology*
Protein Binding
Protein Domains
Respiratory Mucosa / metabolism
SARS-CoV-2
Serine Endopeptidases / genetics
Serine Endopeptidases / metabolism
Spike Glycoprotein, Coronavirus / chemistry
Spike Glycoprotein, Coronavirus / metabolism*
Virus Internalization*

Substances

Antibodies, Monoclonal
NRP1 protein, human
Neuropilin-2
Peptide Fragments
Spike Glycoprotein, Coronavirus
neuropilin-2, human
spike protein, SARS-CoV-2
Neuropilin-1
Peptidyl-Dipeptidase A
ACE2 protein, human
Ace2 protein, mouse
Angiotensin-Converting Enzyme 2
Serine Endopeptidases
TMPRSS2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding