Acute phase human B cell response after ZIKV infection

Abstract

Abstract Prior to its emergence in Brazil in 2015, Zika virus (ZIKV) was mainly reported to cause either asymptomatic infections or mild, self-limiting illness. However, the disease pathology of recent epidemics includes neurological complications such as Guillain-Barré Syndrome in adults and congenital microcephaly in neonates. Consequently, there is a pressing need to understand ZIKV pathogenesis and the immunology of ZIKV infections. To this end, we have studied the B cell response in acutely-infected ZIKV patients, both at the serum and at the monoclonal level. Of the several plasmablast-derived mAbs generated, most were specific to the ZIKV envelope. Given the immunological cross-reactivity between ZIKV and dengue virus (DENV), we tested the panel for reactivity against DENV1-4 and found that all ZIKV-reactive mAbs also bound DENV antigens. Interestingly, even though the patients was infected with ZIKV, more mAbs neutralized DENV than ZIKV in vitro. Patient serum showed high ZIKV and DENV IgG binding titers, illustrating that this cross-reactivity was evident at the serum level as well. At the cellular level, the plasmablasts isolated from these patients exhibited high levels of somatic hypermutation, comparable to frequencies seen in secondary dengue cases. Together, these data suggest that the patients may have previously been exposed to DENV, and that the poorly neutralizing mAbs generated after ZIKV infection could be the product of a DENV-derived memory response, suggesting evidence of original antigenic sin (OAS). These findings have important implications from a public health viewpoint, given that a majority of areas currently experiencing ZIKV outbreaks are also DENV endemic.