# The Fc neonatal receptor and antibody-dependent enhancement of dengue virus infection

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $262,948

## Abstract

PROJECT SUMMARY/ABSTRACT
Dengue virus cause millions of infections and thousands of deaths annually worldwide. Antibody-dependent
enhancement (ADE) is thought to trigger most cases of severe DV infection and is a key consideration in DV
vaccine development. ADE occurs when antibodies elicited by infection with a heterologous DV strain form
immune complexes (ICs) that allow virus entry into endosomes of myeloid cells via Fcγ receptors (FcγRs).
Once within endosomes, successful infection requires a pH-dependent conformational change in the DV
envelope resulting in fusion with late endosomal membranes. Notably, endosomes of myeloid cells reliably
express Fc neonatal receptors (FcRns), which are distinct from FcγRs and which engage IgG at acidic pH and
release it at neutral pH. Thus, in the case of DV ICs, there is an intersection within endosomes between
envelope fusion and engagement of the ICs with FcRn. Until now, however, the effect of such engagement on
ADE has not been studied. Our preliminary data point strongly toward an important role for FcRn in DV ADE,
such that abrogating IC binding to FcRn reduces ADE, whereas increasing IC-FcRn binding increases ADE. In
the proposed research, we will use a novel mouse model to determine if, consistent with our in vitro data, FcRn
engagement with DV ICs increases ADE and the severity of infection outcomes. We will also use in vitro
models to explore potential mechanisms that underlie FcRn involvement in ADE. We will test the following
hypotheses: 1. FcRn engagement by antibodies bound to DV increases the likelihood of ADE and of
severe infection outcomes; and 2. After internalization of DV ICs via FcγRs, FcRn binding results in
retaining infectious ICs in endosomes, thus increasing the likelihood of successful infection. To test
these hypotheses, we will accomplish two specific aims: 1. Determine the impact of human mAbs, with and
without Fc mutations that alter FcRn binding, on the course of DV infection in interferon receptor-deficient
(Ifnar1-/-) mice expressing human FcRn. In addition, we will compare ADE in Ifnar1-/- mice with and without
FcRn expression; 2. Determine the intracellular fate of DV ICs in myeloid cells. The trajectory of DV ICs and
the timing and site of fusion between the virus envelope and endosomal membranes will be tracked by
fluorescence microscopy. This research may lead to new therapeutic strategies for treating severe dengue
virus infections, such as the use of FcRn-blocking antibodies or drugs, and to novel insights into DV vaccine
development. More broadly, if FcRn is mechanistically involved in DV replication in the presence of antibody, it
is very plausible that a similar mechanism might be involved in the replication of any of the several viruses
whose life cycle requires the acidic milieu of the endosome.

## Key facts

- **NIH application ID:** 9877228
- **Project number:** 1R21AI149255-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Donald N Forthal
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $262,948
- **Award type:** 1
- **Project period:** 2020-01-23 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9877228

## Citation

> US National Institutes of Health, RePORTER application 9877228, The Fc neonatal receptor and antibody-dependent enhancement of dengue virus infection (1R21AI149255-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9877228. Licensed CC0.

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