Charge-driven antiviral responses enhance autoreactivity in severe COVID-19

Viral infections are often accompanied by the emergence of antibodies that recognize both viral and self-antigens, a phenomenon largely attributed to molecular mimicry. However, this mechanism does not readily explain the emergence of antiviral antibodies with broad autoreactivity and polyreactivity toward structurally unrelated antigens during acute infection. Here, we demonstrate a charge-driven mechanism underlying the acquisition of autoreactivity by antiviral antibodies. Using BCR sequencing and recombinant antibody cloning from B cells of COVID-19 patients, we found that antiviral antibodies gained autoreactivity through enrichment of positively charged residues in complementarity-determining regions (CDRs). Germline reversion showed that increased spike protein reactivity (S2 domain and RBD) was associated with net positive charge gains in heavy- and light-chain CDRs. Critically, all the positively charged antibodies that gained reactivity to the negatively charged S2 subunit simultaneously increased autoreactivity. Docking and charge mutagenesis of interacting residues confirmed that positive charge is critical for both spike and autoantigen binding. At the population level, antibody repertoires against the more negatively charged Wuhan SARS-CoV-2 spike variant had significantly higher positive charge than those reacting to Omicron variants. Consistently, the charge of hemagglutinin variants and differing subunits drove similar repertoire differences in influenza. Together, these findings identify charge-driven antiviral affinity maturation as a previously unrecognized mechanism linking antiviral immunity to autoreactive antibody generation.