.jpg)
Researchers in the UK have conducted a study demonstrating the importance of considering subdominant epitopes within true respiratory coronavirus 2 (SARS-CoV-2) syndrome when examining neutral antibodies that target the virus.
The SARS-CoV-2 virus is the agent responsible for the 2019 coronavirus outbreak (COVID-19) which continues to pose a threat to global public health and the global economy.
The team from King’s College London, the Francis Crick Institute, and University College London have identified strong neutral antibodies that target epitopes beyond those found in the receptor binding domain (RBD) of the spike protein – the structure the virus uses to bind and infect. cells.
The RBD is the main target for antibody neutralization and several neutral epitopes in the RBD targeted by monoclonal antibodies have been identified and identified.
Katie Doores and her colleagues have now neutralized epitope-targeted antibodies in the spike protein N-terminal domain.
Importantly, the team found that mutations present in the recently discovered B.1.1.7 viral variant counteract neutralization with these specific NTD antibodies.
“This work demonstrates the need to consider the neutralization of antibodies targeting subdominant epitopes when studying antigenic mobility in emerging variants,” the team wrote.
A pre-printed version of the research paper can be found on the bioRxiv* server, while the article is subject to peer review.
The importance of RBD during the infection process
The first step in the SARS-CoV-2 infection process involves the binding of the glycoprotein spike to the host cell receptor angiotensin-converting enzyme 2 (ACE2).
The spike protein consists of two functional subspecies. In subsurface 1 (S1) the NTD and the RBD, which bind to ACE2 use the receptor binding motif (RBM). In subsurface 2 (S2) the peptide is fusion and is responsible for binding the viral membrane to the host cell.
Antibodies targeting the RBD are thought to account for more than 90% of neutral activity against SARS-CoV-2 in convalescent sera. Several RBD epitopes have been targeted to neutralize monoclonal antibodies.
Recent studies have shown that mutations that enable escape of RBD-specific neutralization arise in recently emerged variants of SARS-CoV-2 such as B.1.1.7.
“This highlights the need to identify neutral antibodies that bind epitopes outside of RBD and to understand the role of these antibodies in protection against or after re-infection. the vaccine, “said Doores and crew.
What did the researchers do?
To understand how such mutations may affect the antigenicity of the spike protein, Doores and colleagues developed neutral antibodies targeting epitopes that are longer than those already mentioned. in RBD epitopes.
The team used recombinant spike proteins to separate 107 neutral antibodies from three convalescent donors and identified neutral epitopes present on different regions of the spike.
Forty-seven (43.9%) of these antibodies exhibited neutral activity, and the majority (34; 72.3%) targeted the RBD.
The antibodies targeted epitopes similar to those previously reported, including ACE2-involved epitopes binding the RBM. However, they also focused on epitopes found outside the RBD – in the NTD and S2.
None of the S2-targeted antibodies showed neutral activity, but they were able to react with spike proteins expressed on the surface of the cells.
The team says it will be important to investigate whether these antibodies can exert beneficial actions and participate in viral clearance.
More on antibodies targeting the NTD
Ten (21.3%) of the 47 neutral antibodies targeted NTD. These antibodies were in two distinct groups. One group contained SARS-CoV-2-neutralizing antibodies at the same level as RBD-specific antibodies. The other group exhibited less glycan-dependent neutralization.
Importantly, the team found that while the primary neutral response focused on the RBD, there were mutations in the B.1.1.7 variance that counteracted NTD-specific neutralization.
“As RBD is the main target for neutralizing antibodies after infection, this would suggest specific RBD nAbs [neutralizing antibodies] he had only a limited contribution to escape any immunity contributing to the selection of the B.1.1.7 variant, ”wrote Doores and colleagues.
The team says this demonstrates the importance of considering the neutralization of antibodies targeting subdominant epitopes outside the RBD when identifying SARS-CoV- anxiety changes. 2 reappearing.
“We show that variant B.1.1.7 resists neutralization with the NTD nAbs, highlighting the importance of considering both dominant and subversive neutral epitopes on Spike when they study viral evolution and antigenic movement, ”the team concludes.
* Important message
bioRxiv publish preliminary scientific reports that are not peer-reviewed and, therefore, should not be seen as final, guiding health-related clinical practice / behavior, or be treated as information established.