# Mechanisms of Antibody-Dependent Enhancement of Dengue Disease

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2020 · $423,750

## Abstract

ABSTRACT
Flaviviruses, such as Zika, dengue and West Nile have significant impact on public health with tremendous
socioeconomic consequences for a large fraction of the world's population. A large body of epidemiological data
suggests that susceptibility to dengue disease is strongly associated with prior flavivirus infection, implicating the
presence of cross-reactive, non-neutralizing antibodies as the major disease determinant. This observation has
been confirmed in animal disease models, in which passive administration of flavivirus immune sera or flavivirus-
reactive monoclonal antibodies enhanced disease severity and resulted in increased mortality. These in vivo
studies revealed that the pathogenic activity of antibodies is dependent upon the capacity of their Fc domains to
interact with Fcγ receptors (FcγRs). The currently accepted mechanistic model by which cross-reactive
antibodies contribute to disease pathology is based upon the in vitro observation that IgG antibodies mediate
infection of FcγR-expressing cells through increased uptake of virus-IgG complexes in an FcγR-dependent
manner. This phenomenon has been demonstrated in in vitro assays using primary cells or cell lines of the
myeloid lineage that express only a limited set of human FcγRs. Such experimental conditions do not accurately
reflect the complexity and diversity of FcγR-expressing effector leukocytes present in vivo and it is unclear how
these experimental observations could be related to the biological activities of pathogenic antibodies evident in
animal disease models and in human populations. More importantly, this simplistic model cannot sufficiently
explain why symptomatic dengue disease exhibits so diverse spectrum of clinical phenotypes with varying
disease severity and only a small fraction of symptomatic dengue disease patients progress to severe disease
and ultimately succumbs to death. It is evident that complex host susceptibility factors exist that influence dengue
pathogenesis and determine disease severity. So far, no systematic analysis of the role of FcγRs in the antibody-
mediated disease enhancement during dengue infection has been performed and the precise contribution of
FcγR-mediated pathways is largely unknown, stemming primarily from the lack of a robust in vivo model system
that would mirror precisely the unique complexity of human FcγR biology. The proposed studies aim to dissect
the mechanisms by which Fc-FcγR interactions mediate ADE in vivo and the Fc effector functions that contribute
to dengue disease susceptibility and severity. We anticipate that our findings will significantly advance our
understanding of dengue disease pathogenesis and will have broader impact on the study of other flaviviruses,
like Zika and yellow fever.

## Key facts

- **NIH application ID:** 10168774
- **Project number:** 3R01AI137276-03S1
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Stylianos Bournazos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $423,750
- **Award type:** 3
- **Project period:** 2020-05-18 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168774

## Citation

> US National Institutes of Health, RePORTER application 10168774, Mechanisms of Antibody-Dependent Enhancement of Dengue Disease (3R01AI137276-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10168774. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*