Effect of an Fc Gamma Receptor Polymorphism on Antibody-Dependent Enhancement of Zika Virus Infection

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PROJECT SUMMARY Antibody-dependent enhancement (ADE) is a phenomenon by which antibodies raised in response to a primary infection cross-react to a similar pathogen during a subsequent infection, resulting in increased viral load and severity of disease. ADE of Zika virus (ZIKV) infection by preexisting DENV antibodies has been hypothesized to play a role in the severe adverse pregnancy outcomes observed following congenital ZIKV infection. ADE is mediated by interactions between virus-bound IgG antibodies and Fc gamma receptors (FcRs) on host cells. In humans, a nonsynonymous single nucleotide polymorphism (SNP) in FCGR2A, rs1801274, results in an amino acid change at site 131 from arginine (Arg131) to histidine (His131) in the IgG-binding region of FcRIIA. Previous work in vitro has shown that cells expressing the His131 receptor variant bind human IgG1 and IgG2 with significantly higher affinity than those expressing the Arg131 receptor variant. We hypothesize that individuals homozygous for the high affinity His131 allele will be at greater risk for ADE of viral infection than individuals homozygous for the low affinity Arg131 allele. In this application, we will assess the effect of this SNP on ADE of ZIKV using cell lines derived from K562 cells that are homozygous for the Arg131 or His131 allele and primary human monocytes that will be stratified by genotype (Aim 1). We have also generated IgG subclass switch variants of a flavivirus-reactive monoclonal antibody that we will use to assess the role of each IgG subclass in mediating ADE of ZIKV through the different FcRIIA variants using His131 and Arg131 homozygous K562 cell lines, primary human monocytes, and Hofbauer cells isolated from full term human placentas (Aim 2). A comprehensive understanding of host genetic factors that affect susceptibility to ADE, including those described in this proposal, may help to identify populations at increased risk of developing severe disease as a result of ZIKV infection, particularly among pregnant women. The proposed project provides an excellent opportunity for training that encapsulates traditional virology and immunology techniques, professional development, and mentorship that will support the applicant’s growth as an independent academic scientist.