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Authors: Cantuti-Castelvetri et al. 

Journal/ Pre-Print:     bioRxiv 

Tags: Bioinformatics, Cell Biology, Clinical, Molecular biology, Virology 

Research Highlights 

  1. Cellular receptor neuropilin-1 (NRP1) potentiates SARS-CoV-2 infectivity. 

  1. NRP1 is expressed in respiratory and olfactory epithelium and SARS-CoV-2 infected NRP1-positive cells are found in the olfactory epithelium and bulb of COVID-19 patients.   

  1. In mice experiments, NRP1 can mediate the transport of virus-sized particles into the central nervous system through the olfactory system. 

Summary 

SARS-CoV-2, in comparison to SARS-CoV, contains a furin-type cleavage site in its spike protein, which when cleaved can bind and activate neuropilin receptors (NRP1 and NRP2). The authors show that NRP1 enhances SARS-CoV-2 infectivity. This effect is decreased with an antibody against NRP1 or use of SARS-CoV-2 with a mutated furin cleavage site. NRP1 is expressed in respiratory and olfactory epithelium. In COVID-19 patients, SARS-CoV-2 was found in NRP1-positive cells of the olfactory epithelium and in the olfactory bulb and tracts. Mice experiments show that the NRP1-positive cells of the olfactory system can mediate the transport of virus-sized particles to the central nervous system, potentially explaining some clinical symptoms such as the loss of olfaction. 

Impact for SARS-CoV2/COVID19 research efforts   

Understand the virology and/or cell biology of SARS-CoV2/COVID19 

Clinical symptoms and pathogenesis of SARS-CoV2/COVID19 

Inhibit of SARS-CoV2/COVID19 transmission 

Study Type  

  • Bioinformatics study 

  • In vitro study 

  • In vivo study (mouse) 

  • Patient Case study (IHC in COVID-19 patient samples and 7 non-infected controls)  

Strengths and limitations of the paper 

Novelty: Discovery of a cellular receptor, NRP1, which binds furin-cleaved substrates, that potentiates SARS-CoV-2 infectivity. As NRP1 is expressed in respiratory and olfactory epithelium, it could explain the effect of SARS-CoV-2 infection on the disturbance of sense olfaction. This is supported by the presence in COVID-19 patients of SARS-CoV-2 in NRP1-positive cells in olfactory epithelial cells. This could also explain the difference in tropism of SARS-CoV and SARS-CoV-2. In mice experiments, the authors also show that the olfactory epithelial could serve as a viral entry to the brain.     

Standing in the field:Another bioRxiv preprint (Daly et al, 2020) also shows with different techniques that NRP1 enhances SARS-CoV-2 infection. In addition, they found that the same antibody against NRP1, mAb3, also decreases SARS-CoV-2 infection.  

Appropriate statistics: Yes 

Viral model used:Wild-type SARS-CoV-2 and mutant SARS-CoV-2, which has a deletion at the furin-cleavage site. 

Translatability:An antibody against NRP1, mAb3, decreases wild-type SARS-CoV-2 infectivity, which could potentially be clinically useful. However, NRP1 has other ligands, increasing the risk of off-target effects.  

Main limitations: The two preprints, this one and Daly et al, 2020, together provide strong evidence that SARS-CoV-2 uses NRP1 in addition to ACE2 and TMPRSS2 as host factors (from in vitro to mice and COVID-19 patients). However, only one antibody against NRP1, mAb3, was found in both studies to decrease SARS-CoV-2 infectivity, which can potentially be problematic is mAb3 has off-target effects that can indirectly affect SARS-CoV-2 infectivity.   

As the authors mention in the discussion, this study does not give an insight into the exact role of NRP1 in viral entry (e.g. whether it acts as a receptor only, mediates S protein cleavage etc.). Also, this study only looks at olfactory epithelium and the CNS, rather than other respiratory tissues associated with the more severe clinical symptoms of COVID-19, particularly the lung.