SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity
Annachiara Rosa, Valerie E. Pye, Carl Graham, Luke Muir, Jeffrey Seow, Kevin W. Ng, Nicola Cook, Chloe Rees-Spear, Eleanor Parker, Mariana Silva dos Santos, Carolina Rosadas, Alberto Susana, Hefin Rhys, Andrea Nans, Laura Masino, Chloë Roustan, Evangelos Christodoulou, Rachel Ulferts, Antoni G. Wrobel, Charlotte‐Eve Short, Michael Fertleman, Rogier W. Sanders, Judith Heaney, Moira Spyer, Svend Kjær, Andrew Riddell, Michael H. Malim, Rupert Beale, James I. MacRae, Graham P. Taylor, Eleni Nastouli, Marit J. van Gils, Peter B. Rosenthal, Massimo Pizzato, Myra O. McClure, Richard S. Tedder, George Kassiotis, Laura E. McCoy, Katie J. Doores, Peter Cherepanov
Abstract
The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo-electron microscopy and x-ray crystallography, we 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. Our results 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 recruitment of a metabolite.