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A monoclonal antibody against staphylococcal enterotoxin B superantigen inhibits SARS-CoV-2 entry in vitro
Mary Hongying Cheng1, Rebecca A Porritt2, Magali Noval Rivas2
1Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Abstract:
We recently discovered a superantigen-like motif sequentially and structurally similar to a staphylococcal enterotoxin B (SEB) segment, near the S1/S2 cleavage site of the SARS-CoV-2 spike protein, which might explain the multisystem inflammatory syndrome (MIS-C) observed in children and the cytokine storm in severe COVID-19 patients. We show here that an anti-SEB monoclonal antibody (mAb), 6D3, can bind this viral motif at its polybasic (PRRA) insert to inhibit infection in live virus assays. The overlap between the superantigenic site of the spike and its proteolytic cleavage site suggests that the mAb prevents viral entry by interfering with the proteolytic activity of cell proteases (furin and TMPRSS2). The high affinity of 6D3 for this site originates from a polyacidic segment at its heavy chain CDR2. The study points to the potential utility of 6D3 for possibly treating COVID-19, MIS-C, or common colds caused by human coronaviruses that also possess a furin-like cleavage site.
Insights
A novel superantigen-like motif on SARS-CoV-2 spike protein may cause MIS-C and severe COVID-19. An anti-SEB antibody (6D3) inhibits viral infection by blocking this motif and protease activity.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- SARS-CoV-2 spike protein contains a superantigen-like motif similar to staphylococcal enterotoxin B (SEB).
- This motif is located near the S1/S2 cleavage site, a region crucial for viral entry and pathogenesis.
- The motif's presence may explain severe COVID-19 manifestations like cytokine storm and multisystem inflammatory syndrome in children (MIS-C).
Purpose of the Study:
- To investigate the role of the SEB-like motif in SARS-CoV-2 pathogenesis.
- To evaluate the efficacy of an anti-SEB monoclonal antibody (mAb), 6D3, in inhibiting SARS-CoV-2 infection.
- To explore the therapeutic potential of mAb 6D3 for COVID-19 and related inflammatory syndromes.
Main Methods:
- Structural and sequential analysis of the SARS-CoV-2 spike protein to identify superantigen-like motifs.
- In vitro live virus assays using mAb 6D3 to assess its inhibitory effect on viral infection.
- Analysis of mAb 6D3's binding site and affinity to the viral motif, including its heavy chain CDR2 region.
Main Results:
- A superantigen-like motif, structurally and sequentially similar to SEB, was identified on the SARS-CoV-2 spike protein near the S1/S2 cleavage site.
- The anti-SEB mAb 6D3 effectively binds to this viral motif, specifically at the polybasic (PRRA) insert.
- mAb 6D3 demonstrated inhibition of SARS-CoV-2 infection in live virus assays, suggesting interference with proteolytic cleavage by host proteases (furin and TMPRSS2).
- The high affinity of 6D3 is attributed to a polyacidic segment in its heavy chain CDR2.
Conclusions:
- The identified superantigen-like motif on the SARS-CoV-2 spike protein is a potential contributor to severe COVID-19 and MIS-C.
- The anti-SEB mAb 6D3 shows promise as a therapeutic agent by inhibiting viral entry through dual action on the motif and protease activity.
- mAb 6D3 may offer a potential treatment strategy for COVID-19, MIS-C, and other human coronavirus infections with similar cleavage site characteristics.
