• Why is SARS-CoV-2 so virulent?

    Posted on Nov 20, 2020

    SARS-CoV-2 is more virulent than SARS-CoV (identified in 2003), because it binds to host cells with greater affinity, and more recently (see below) uses another receptor to increase virus uptake into cells.

    The second binding receptor, Neuropilin-1, (NRP1) has been discovered for the SARS-CoV-2 (1). This receptor is more prevalent on more tissues than the ACE2 receptor. NRP1 is not only in the lining of the respiratory tract but also in the lining of blood vessels and the surface of neurons. This additional avenue of infection may help to explain why SARS-CoV-2 is so much more effective and transmissible than other coronaviruses and how it is able to infect organs outside the respiratory system, e.g., the brain and heart.

    Binding of SARS-CoV-2 to Neuropilin-1
    Now it is known that once the Spike protein (S) binds to the ACE2, it is cleaved into 2 non-convalently associated subunits, S1 and S2. The S1 can bind to another cell-surface transmembrane receptor, Neuropilin-1. The authors of the Science manuscript(1) used various biochemical techniques as well as X-ray crystallography to demonstrate that the S1 directly binds NRP1.

    Mechanism of Infection and Internalization
    In a series of cell culture experiments, cells expressing ACE2 but lacking NRP1 displayed lower levels of infection following viral exposure than cells with both receptor types. Cells with neither ACE2 nor NRP1 did not become infected. In the presence of ACE2 but the absence of NRP1, the virus still bound to host cell surface, but the rate of internalization was halved.

    The researchers said that because binding of S1 to NRP1 does not affect cell surface attachment of the virus, it does promote entry and infection of susceptible cell lines. The mechanism by which the virus enters cells based on the interaction of S1 with the NRP1 receptors is still unclear. However, they offered macro-pinocytosis, a nonspecific uptake of extracellular material that neuropilins are known to mediate, as one possibility for how the virus might enter NRP1+ cells.

    Possible Therapy Routes by Blocking the S1-NRP1 interaction
    The scientists were able to block the interaction between the S1 subunit and NRP1 receptors and reduce the ability of the virus to infect human cells in culture using either monoclonal antibodies or suppressor shRNA. They also demonstrated binding of a small molecule NRP1 inhibitor to the binding pocket of NRP1 resulted in lowered levels of infection following virus exposure. These experimental results indicate potential avenues for the development of therapies to fight COVID-19 infection by blocking S1-NRP1 binding.

    Comparisons with SARS-CoV
    The team also noted that the sequence that binds NRP1 is not a component of the S protein of SARS-CoV, the previous version of this coronavirus. Because NRP1 binding by the earlier virus does not occur, NRP1 is thus likely to play a role in the increased infectivity of SARS-CoV-2 compared with SARS-CoV. The authors also made reference in their conclusion to clinical data from other groups showing upregulation of NRP1 in lung tissue from COVID-19 patients and said that the ability to target this specific interaction could provide a route for COVID-19 therapies.

    (1) Daly JL, Simonetti B, Klein K, et al. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science, Oct. 20, 2020; DOI: 10.1126/science.abd3072

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