Breaking News! Study Shows Human Haem Metabolites Biliverdin And Bilirubin Blocks The Binding Of Neutralizing Antibodies To SARS-CoV-2
: A new study by researchers from the Francis Crick Institute, in collaboration with researchers from the Imperial College London, Kings College London and UCL (University College London), found that biliverdin and bilirubin, which are natural molecules present in the body, can suppress the binding of antibodies to the coronavirus spike.
According to the study team, the coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies.
The team showed that SARS-CoV-2 spike binds to both biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity.
Utilizing cryo-electron microscopy and X-ray crystallography, the team mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite.
The study findings indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through the recruitment of a metabolite.
The study findings were published in the peer reviewed journal: Science Advances
The study team found that these natural molecules can effectively block the binding of a subset of human antibodies to SARS-CoV-2. The discovery may help explain why some COVID-19 patients can become severely ill despite having high levels of antibodies against the virus.
The team found that biliverdin and bilirubin, natural molecules present in the body, can suppress the binding of antibodies to the coronavirus spike.
While various COVID-19 vaccines are rolled out globally, understanding immunity to SARS-CoV-2 and also how the virus evades antibodies is critically important.
To date there are still many unknowns. The ability of the immune system to control the infection and the quality of the antibody response are highly variable, and not well correlated, between individuals.
The team from the Francis Crick Institute was involved in the development of tests that see if a person has been exposed to the virus.
The researchers discovered that the SARS-CoV-2 spike protein strongly binds to biliverdin, a molecule which was giving these proteins an unusual green coloration.
Along with teams at Imperial College London, UCL and Kings College London, they found that this natural molecule reduced antibody binding to the spike.
The study team used blood sera and antibodies from individuals who were previously infected with SARS-CoV-2 and found that biliverdin could suppress the binding of human antib
odies to the spike by as much as 30-50%, with some antibodies becoming ineffective at neutralizing the virus.
Interestingly such a significant impact was completely unexpected, as biliverdin only binds to a very small patch on the virus' surface. To find out the mechanism at work, the team at the Crick used cryo-electron microscopy and X-ray crystallography to look in detail at the interactions between the spike, the antibodies and biliverdin.
The team found that biliverdin attaches to the spike N-terminal domain and stabilizes it so that the spike is not able to open up and expose parts of its structure. This means that some antibodies are not able to access their target sites and so cannot bind to and neutralize the virus.
Dr Annachiara Rosa, study first author and postdoctoral training fellow, Chromatin Structure and Mobile DNA Laboratory, Francis Crick Institute told Thailand Medical News, “When SARS-CoV-2 infects a patient's lungs it damages blood vessels and causes a rise in the number immune cells. Both of these effects may contribute to increasing the levels of biliverdin and bilirubin in the surrounding tissues. And with more of these molecules available, the virus has more opportunity to hide from certain antibodies. This is a really striking process, as the virus may be benefiting from a side-effect of the damage it has already caused."
Dr Peter Cherepanov, author and a group leader of the Chromatin structure and mobile DNA Laboratory at the Crick, added, "In the first months of the pandemic, we were extremely busy churning out viral antigens for SARS-CoV-2 tests.It was a race, as these tests were urgently needed. When we finally found the time to study our green proteins, we expected a mundane answer. Instead, we were astonished to discover a new trick the virus uses to avoid antibody recognition. This is a result of a collaborative effort of several amazing teams working at the Crick and three partner universities, led purely by scientific curiosity."
The study team will continue this work from various angles, including measuring the levels of biliverdin and other haem metabolites in patients with COVID-19 and also exploring if it is possible to hijack the binding site used by biliverdin to potentially find new ways to target the virus.
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