Sustained antibody response to ZIKV infection induced by NS1 protein is accompanied by the progressive appearance of autoreactive antibodies and cross-reactive B cell clones

Cavazzoni, Cecilia B.; Bozza, Vicente B. T.; Tostes, Lucas; Maia, Bruno; Mesin, Luka; Schiepers, Ariën; Ersching, Jonatan; Neris, Romulo L.S.; Conde, Jonas N.; Coelho, Diego R.; Conde, Luciana; de Paula Neto, Heitor A.; Lima, Tulio M.; Alvim, Renata G.F.; Castilho, Leda R.; Mohana-Borges, Ronaldo; Assunção-Miranda, Iranaia; Nobrega, Alberto; Victora, Gabriel D.; Vale, Andre M.

Besides antigen-specific responses to viral antigens, humoral immune response in virus infection can generate polyreactive and autoreactive antibodies. Dengue and Zika virus infections have been linked to antibody-mediated autoimmune disorders including Guillain-Barrè syndrome. A unique feature of flaviviruses is the secretion of non-structural protein 1 (NS1) by infected cells. NS1 is highly immunogenic and antibodies targeting NS1 can have both protective and pathogenic roles. In the present study, we investigated the humoral immune response to Zika virus NS1 and found NS1 to be an immunodominant viral antigen associated with the presence of autoreactive antibodies. Through single B cell cultures, we coupled binding assays and BCR sequencing, confirming the immunodominance of NS1. Of note, we demonstrate the presence of self-reactive clones in germinal centers after both infection and immunization, some of which clones presenting cross-reactivity with NS1. Sequence analysis of anti-NS1 B cell clones showed sequence features associated with pathogenic autoreactive antibodies. Our findings demonstrate NS1 immunodominance at the cellular level as well as a potential role for NS1 in ZIKV associated autoimmune manifestations.