# Mechanisms of Antibody-Dependent Enhancement of Dengue Disease

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2024 · $459,711

## Abstract

ABSTRACT
Instead of conferring protection, IgG antibodies against dengue virus (DENV) have been correlated with
increased susceptibility to symptomatic dengue disease, as patients with pre-existing antibodies against DENV
experience at a higher rate the symptomatic form of dengue disease, which often includes life-threatening
complications. With over 2.5 billion people being at risk of DENV infection and with >100 million new infections
occurring annually, DENV represents a tremendous burden to global human public health, necessitating the
development of efficacious therapeutic or vaccination approaches to control DENV infection and disease. Using
in vitro cellular assays, several studies have previously suggested that anti-DENV antibodies can mediate
enhanced viral infection of Fcγ receptor (FcγR)-expressing myeloid cells; a phenomenon referred to as antibody
dependent enhancement (ADE). However, ADE of viral replication alone cannot account for the complex
pathophysiological features of symptomatic dengue disease, as well as for the wide spectrum of clinical disease
severity observed among symptomatic patients. During the previous funding period, in collaborative studies with
the Institute Pasteur in Cambodia, a DENV endemic area, we demonstrated that dengue disease susceptibility,
as well as disease severity are associated with the induction of specific glycoforms of IgG antibodies
(afucosylated) that exhibit increased affinity for the activating FcγRIII receptor. In parallel mechanistic studies,
we developed a novel in vivo model of dengue disease that expresses the full array of human FcγRs and is
permissive for DENV infection. Using this model, we demonstrated that a critical step in the in vivo pathogenesis
of dengue disease is the engagement of FcγRIIIa on macrophages by afucosylated IgG antibodies, which are
enriched in severe dengue cases. FcγRIIIa-afucosylated IgG antibody interactions result in aberrant macrophage
activation, inflammatory sequelae, significant morbidity, and mortality. These findings implicate the FcγRIIIa-
afucosylated Fc axis as the basis for dengue disease susceptibility and pathogenesis. Using a unique set of
biospecimens from DENV-infected patients, as well as our recently developed mouse models of ADE of dengue
disease, the proposed studies aim to (i) dissect the mechanisms that drive the induction of IgG Fc afucosylated
glycoforms upon DENV infection and (ii) characterize the downstream effector responses that are initiated upon
engagement of FcγRIIIa by afucosylated IgG antibodies and contribute to disease pathogenesis. We anticipate
that our findings will significantly advance our understanding of the pathways that regulate IgG Fc glycan
heterogeneity during DENV infection and drive dengue disease pathogenesis, having a broader impact on the
study of immune responses against other viral pathogens that are characterized by aberrant IgG Fc fucosylation.

## Key facts

- **NIH application ID:** 10870026
- **Project number:** 5R01AI137276-07
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Stylianos Bournazos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $459,711
- **Award type:** 5
- **Project period:** 2018-09-24 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10870026

## Citation

> US National Institutes of Health, RePORTER application 10870026, Mechanisms of Antibody-Dependent Enhancement of Dengue Disease (5R01AI137276-07). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10870026. Licensed CC0.

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