Cross-regulation of antibody responses against the SARS-CoV-2 Spike protein and commensal microbiota via molecular mimicry

• Published in: Cell host & microbe 2023-11, Vol.31 (11), p.1866-1881.e10
• Main Authors: Bondareva, Marina, Budzinski, Lisa, Durek, Pawel, Witkowski, Mario, Angermair, Stefan, Ninnemann, Justus, Kreye, Jakob, Letz, Philine, Ferreira-Gomes, Marta, Semin, Iaroslav, Guerra, Gabriela Maria, Momsen Reincke, S., Sánchez-Sendin, Elisa, Yilmaz, Selin, Sempert, Toni, Heinz, Gitta Anne, Tizian, Caroline, Raftery, Martin, Schönrich, Günther, Matyushkina, Daria, Smirnov, Ivan V., Govorun, Vadim M., Schrezenmeier, Eva, Stefanski, Anna-Luisa, Dörner, Thomas, Zocche, Silvia, Viviano, Edoardo, Klement, Nele, Sehmsdorf, Katharina Johanna, Lunin, Alexander, Chang, Hyun-Dong, Drutskaya, Marina, Kozlovskaya, Liubov, Treskatsch, Sascha, Radbruch, Andreas, Diefenbach, Andreas, Prüss, Harald, Enghard, Philipp, Mashreghi, Mir-Farzin, Kruglov, Andrey A.
• Format: Article
• Language: English
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2023.10.007

The commensal microflora provides a repertoire of antigens that illicit mucosal antibodies. In some cases, these antibodies can cross-react with host proteins, inducing autoimmunity, or with other microbial antigens. We demonstrate that the oral microbiota can induce salivary anti-SARS-CoV-2 Spike IgG antibodies via molecular mimicry. Anti-Spike IgG antibodies in the saliva correlated with enhanced abundance of Streptococcus salivarius 1 month after anti-SARS-CoV-2 vaccination. Several human commensal bacteria, including S. salivarius, were recognized by SARS-CoV-2-neutralizing monoclonal antibodies and induced cross-reactive anti-Spike antibodies in mice, facilitating SARS-CoV-2 clearance. A specific S. salivarius protein, RSSL-01370, contains regions with homology to the Spike receptor-binding domain, and immunization of mice with RSSL-01370 elicited anti-Spike IgG antibodies in the serum. Additionally, oral S. salivarius supplementation enhanced salivary anti-Spike antibodies in vaccinated individuals. Altogether, these data show that distinct species of the human microbiota can express molecular mimics of SARS-CoV-2 Spike protein, potentially enhancing protective immunity.