SARS-CoV-2 recruits a haem metabolite to evade antibody immunity

ABSTRACT

Background: Understanding antibody immunity to SARS-CoV-2 and how the virus evades it is of critical importance in the fight against COVID-19. Our best hope of ending the pandemic is antibody-inducing vaccination, yet the precise targets and indeed protective capacity of antibodies remain incompletely defined. The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We discovered neutralizing epitopes located on the distal face of the SARS-CoV-2 spike N-terminal domain (NTD). Remarkably, instead of glycosylation, the virus uses a surface-exposed loop to restrict the access to this patch, and the gate is controlled through recruitment and dissociation of a metabolite. Methods: Using cryo-electron microscopy and X-ray crystallography we mapped a tetrapyrrole binding site to a deep cleft on the spike N-terminal domain (NTD, Fig. 1) and characterized structural features of a neutralizing epitope controlled by metabolite dissociation. Results: We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity in a pH-sensitive manner. 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. Conclusion: It is well-established that viruses employ extensive glycosylation of their envelopes to shield antibody epitopes. Compared to glycosylation, epitope masking via metabolite recruitment has the advantage of reversibility. For instance, pH-dependence of the spike-tetrapyrrole interaction potentially allows dissociation within the late endosomal compartment. In summary, our results 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.