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

Antibodies are key players in controlling viral infections. However, in addition to antigen-specific responses to viral antigens, humoral immune response can generate polyreactive and autoreactive antibodies of unknown function. Dengue and Zika virus infections have been linked to autoimmune disorders including Guillain-Barre 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 correlated to the presence of autoreactive antibodies. Through single B cell cultures, we coupled binding assays and BCR sequencing, confirming the immunodominance of NS1 and the presence of self-reactive clones in germinal centers both after infection and immunization, some of which were cross-reactivity with NS1. Anti-NS1 B cell clones showed features related to 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.