Researchers find natural metabolites help SARS-CoV-2 escape antibodies

By Jocelyn Solis-MoreiraJun 2 2021

An international team of scientists has identified a human molecule — biliverdin — as a potential severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) target. The binding of the heme metabolite to the N-terminal domain of SARS-CoV-2 is associated with the virus’s ability to dodge the immune system by suppressing antibody binding to the spike protein.

“Although more work is required to validate this model, our results suggest that biliverdin binding may impair the sensitivity of SARS-CoV-2 immunoassays. Furthermore, it would be of interest to evaluate spike constructs deficient for the interaction with tetrapyrroles as vaccine candidates. Our results demonstrate a remarkable structural plasticity of the NTD and highlight the importance of this domain for antibody immunity against SARS-CoV-2,” wrote the research team.

Previous work has shown mutations within the N-terminal domain are linked to increased immune evasion. A mutation that causes a higher binding affinity between the spike protein and the metabolized heme molecule could increase the risk of a weaker neutralizing antibody response. Future work will need to focus on whether the binding site between biliverdin and SARS-CoV-2 can be targeted and hijacked for future treatments.

The study “SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity” was recently published in the journal Science Advances.

Study: SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity. Image Credit: NIAID

How they did it

The researchers collected blood serum and antibodies from people who recovered from COVID-19 infection to measure the level of neutralizing antibodies specific for SARS-CoV-2 and metabolite binding.

The researchers also used cryo-electron microscopy and X-ray crystallography to study structural changes and molecular interactions to understand how biliverdin binding affects neutralizing antibody response.

Biliverdin induces conformational changes to the N-terminal domain

Results showed biliverdin binds and stabilizes the N-terminal domain of the SARS-CoV-2 spike protein through an allosteric mechanism. The neutralizing antibodies require relocation of the gating loop but biliverdin’s attachment prevents the antibody’s targeting site from being exposed.

“To allow P008_056 binding, the loop swings out of the way, with a backbone displacement in the middle of the loop of ~15 Å. The gating mechanism is accompanied by insertion of Phe175 and Met177, which are located in the beginning of the loop, into the hydrophobic pocket vacated by biliverdin. Thus, when bound, the metabolite appears to act as a wedge that restricts gate opening.”

It also makes the viral envelope glycoprotein refractory to neutralization.

The neutralizing antibodies require an upward movement of a beta-hairpin overlaying a cluster of aromatic residues. While both loop regions are variable by themselves, the presence of biliverdin makes it harder for them to show up.

Decreased effectiveness of neutralizing antibodies in the presence of biliverdin

Two monoclonal antibodies, COVA1-22 and COVA2-17, were most affected by biliverdin’s binding to the N-terminal domain. Its presence weakened the wild-type SARS-CoV-2 strains.

The researchers suggest the heme metabolite could help hide the antigenic properties of the virus by causing it to unmask only under certain conditions — potentially further increasing the difficulty of antibody binding.

Results show biliverdin is present at higher molar concentrations than antibody binding — suggesting the level of the heme metabolite in the body is important in inhibiting some neutralizing antibody responses.

“In addition, tetrapyrrole levels are likely to vary between anatomical locations and during the course of natural infection, explaining the emergence of the biliverdin-sensitive antibody Fraction,” explained the researchers.

The presence of the heme metabolite in the body is likely during COVID-19 infection. While metabolite levels were not directly measured during an infection, the researchers infer the metabolite could be a product of neutrophil myeloperoxidase from nasopharyngeal swabs used for COVID testing or activation heme oxygenase during lung inflammation.