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Source: Research News  Jan 28, 2021  10 months ago
Research News: Study By Francis Crick Institute Shows That Biliverdin Protects SARS-CoV-2 From Human Host Antibody Response
Research News: Study By Francis Crick Institute Shows That Biliverdin Protects SARS-CoV-2 From Human Host Antibody Response
Source: Research News  Jan 28, 2021  10 months ago
Research News: A new international study led by scientists from Francis Crick Institute involving numerous other research institutions has revealed that the SARS-CoV-2 coronavirus  interacts with two heme metabolites, bilirubin and biliverdin, to escape the antibody-mediated host immune responses.

According to the study abstract, “The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. The study team shows that the SARS-CoV-2 spike binds to biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity. Utilizing cryo-electron microscopy and X-ray crystallography the study 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 the virus co-opts the haem metabolite for the evasion of humoral immunity via allosteric shielding of a sensitive epitope and demonstrate the remarkable structural plasticity of the NTD.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2021.01.21.21249203v1
It is already known that the cellular entry of SARS-CoV-2, the causative pathogen of COVID-19, is initiated by the interaction between the viral spike protein and the host angiotensin-converting enzyme 2 (ACE2). The spike protein is the most immunogenic component of SARS-CoV-2, and thus, the most potent target of neutralizing antibodies. While it is known that the receptor-binding domain (RBD) at the C-terminal end of spike S1 subunit interacts with ACE2, the structure and function of the spike N-terminal domain is largely unknown.
The study team in this research aimed to evaluate the immunogenic properties of the N-terminal domain of the SARS-CoV-2 spike protein.

The study team produced a range of recombinant spike antigens using human cell lines as a part of the serological analysis of SARS-CoV-2,  During the analysis of these constructs, the scientists noticed a distinctive spectrum of trimeric spike and S1 subunit that is similar to the spectrum of a heme metabolite, biliverdin.
Also to investigate further, the team isolated the pigment from the S1 subunit and confirmed the presence of biliverdin by mass spectrometry.
The green tetrapyrrolic bile pigment biliverdin is the initial breakdown product of heme, which is further reduced to produce bilirubin.
Utilizing surface plasmon resonance, the study team examined the binding of bilirubin and biliverdin to the spike S1 subunit and observed that spike S1 has a strong affinity for biliverdin.
Further structural analysis using cryo-electron microscopy revealed that biliverdin is positioned within a deep cleft on the spike N-terminal domain.
Detailed analysis revealed that the binding pocket of biliverdin is surrounded by hydrophobic residues that interact with the ligand.
As a histidine residue is present in the biliverdin binding pocket, the study team hypothesized that the interaction between S1 and biliverdin may be pH-dependent.
In line with the hypothesis, they noticed a significant reduction in biliverdin content of the S1 subunit under acidic pH. Interestingly, the substitution of amino acids closely involved in ligand binding resulted in 2- to 3-fold reduction in biliverdin-S1 binding affinity. However, they observed that the SARS-CoV-2 spike containing these amino acid substitutions is still capable of infecting cells, indicating that biliverdin binding is not associated with viral entry.
In order to investigate the immunological consequences of biliverdin-S1 binding, they measured the reactivity of anti-SARS-CoV-2 human sera with wild-type and N121Q mutated spike protein using flow cytometry.
The study findings revealed that biliverdin significantly reduces the binding of anti-SARS-CoV-2 IgG antibodies to the wild-type spike protein. However, biliverdin could not change the affinity of antibodies toward N121Q mutated spike protein.
From this remarkable observation on antigen-antibody binding, the study team further evaluated the binding affinity of a panel of anti-SARS-CoV-2 IgGs cloned from B cells of COVID-19 recovered individuals toward wild-type and N121Q mutated spike protein.
These findings revealed that about 17% of IgGs fail to bind with wild-type spike protein in presence of biliverdin. Interestingly, biliverdin could not affect the binding efficiency of antibodies developed specifically against the spike RBD.
Importantly, it was observed that biliverdin significantly reduces the neutralization of SARS-CoV-2 by a panel of neutralizing antibodies.
Pertaining to the mode of action of biliverdin, the study team noticed that by binding to the S1 pocket, biliverdin restricts the relocation of the gating loop required for antibody binding to its epitope. In other words, biliverdin prevents the spike- antibody binding by restricting the conformational remodeling of the spike N-terminal domain.
The study tea concluded, “The study reveals that biliverdin, a heme metabolism product, can facilitate SARS-CoV-2 to escape antibody-mediated host immune responses. Moreover, the study identifies a neutralizing epitope on the spike N-terminal domain that is differentially exposed to neutralizing antibodies based on the recruitment of biliverdin.”
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Feb 05, 2020  2 years ago
Source : Thailand Medical news