The possible role of cross-reactive dengue virus antibodies in Zika virus pathogenesis

Abstract

Zika virus (ZIKV) has been known for decades to circulate in Africa and Asia. However, major complications of a ZIKV infection have recently become apparent for reasons that are still not fully elucidated. One of the hypotheses for the seemingly increased pathogenicity of ZIKV is that cross-reactive dengue antibodies can enhance a ZIKV infection through the principle of antibody-dependent enhancement (ADE). Recently, ADE in ZIKV infection has been studied, but conclusive evidence for the clinical importance of this principle in a ZIKV infection is lacking. Conversely, the widespread circulation of ZIKV in dengue virus (DENV)-endemic regions raises new questions about the potential contribution of ZIKV antibodies to DENV ADE. In this review, we summarize the results of the evidence to date and elaborate on other possible detrimental effects of cross-reactive flavivirus antibodies, both for ZIKV infection and the risk of ZIKV-related congenital anomalies, DENV infection, and dengue hemorrhagic fever.

Fig 1. Proposed mechanism of ADE of ZIKV infection mediated by cross-reactive anti-DENV antibodies.

(A) Primary ZIKV infection in naïve individuals. Entry occurs via other receptors and leads to virus and cytokine production. (B) Secondary ZIKV infection in a ZIKV-preimmune individual. Neutralization occurs effectively. (C) ZIKV ADE (black antibodies; preexisting antibodies against primary infecting DENV) Abs in immune sera can cross-react with ZIKV, allowing entry of the virus–antibody complexes into MPCs via the Fc receptor, leading to higher viral load along with higher levels of pro- and/or anti-inflammatory cytokines than cells infected in absence of antibodies. Ab, antibody; ADE, antibody-dependent enhancement; DENV, dengue virus; Fc, fragment crystallizable; MPC, mononuclear phagocytic cell; ZIKV, Zika virus.

Fig 2. Results from in vivo studies investigating the role of ZIKV antibodies in DENV infection and on DENV antibodies in ZIKV infection.

Left panel: In mice that had ZIKV antibodies either maternally acquired or administered before DENV infection, increased DENV viral load, cytokine production, and mortality was observed. In macaques that were previously infected with ZIKV, an increased DENV viral load but no clinical symptoms or mortality was observed upon infection with DENV. Right panel: In some DENV-preimmune mice that were infected with ZIKV, an increased viral load and cytokine production but not mortality was observed. In DENV-preimmune macaques infected with ZIKV, no changes in viral load, cytokine production, or mortality was observed in DENV. ADE, antibody-dependent enhancement; DENV, dengue virus; ZIKV, Zika virus.

Fig 3. Proposed mechanism of FcRn-mediated transcytosis of a ZIKV–IgG complex in a chorionic villus.

Illustrated is a chorionic villus that is anchored to the mucosal lining of the uterus (decidua). Through the circulation of the mother, ZIKV bound to maternal cross-reactive flavivirus IgG antibodies is present in the intervillous space. This IgG–virion complex can subsequently cross the syncytiotrophoblasts via FcRn-mediated transcytosis. When ZIKV is transcytosed across this trophoblast layer, it can infect the perivascular-located Hofbauer cells, after which viral progeny can cross the endothelial cell barrier, possibly with help from ZIKV NS1 protein, and reach the fetal circulation. FcRn, neonatal fragment crystallizable receptor; IgG, immunoglobulin G; NS1, nonstructural protein 1; ZIKV, Zika virus.