NK Cells Activated through Antibody-Dependent Cell Cytotoxicity and Armed with Degranulation/IFN-\u03b3 Production Suppress Antibody-dependent Enhancement of Dengue Viral Infection

Peifang Sun,Brian J Morrison,Maya Williams,Nishith Nagabhushana,Vihasi Jani,Gabriel Defang

doi:10.1038/s41598-018-36972-2

Peifang Sun, Brian J Morrison + Show 4 more

Open Access

https://doi.org/10.1038/s41598-018-36972-2

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Abstract

Antibody (Ab)-dependent enhancement (ADE) is a hypothesized mechanism of increased disease severity during secondary dengue virus (DENV) infection. This study investigates Ab-dependent cell cytotoxicity (ADCC) in counteracting ADE. In our system, DENV and DENV-immune sera were added to peripheral blood mononuclear cells (PBMCs), and ADE and NK cell activation were simultaneously monitored. ADE was detected in monocytes and a concurrent activation of NK cells was observed. Activated NK cells expressed IFN-γ and CD107a. IFN-γ was detected at 24 hours (24 h) followed by a rapid decline; CD107a expression peaked at 48 h and persisted for >7 days. Optimal activation of NK cells required the presence of enhancement serum together with ADE-affected monocytes and soluble factors, suggesting the coexistence of the counteractive ADCC Abs, in the same ADE-serum, capable of strongly promoting NK cell activation. The function of NK cells against ADE was demonstrated using a depletion assay. NK cell-depleted PBMCs had increased ADE as compared to whole PBMCs. Conversely, adding activated NK cells back into the NK-depleted-PBMCs or to purified monocytes decreased ADE. Blocking IFN-γ expression also increased ADE. The study suggests that under ADE conditions, NK cells can be activated by ADCC Abs and can control the magnitude of ADE.

Highlights

Antibody (Ab)-dependent enhancement (ADE) is a hypothesized mechanism of increased disease severity during secondary dengue virus (DENV) infection
We hypothesized that the elimination of ADE-affected cells could be the major task early on for the host system via an Ab-dependent cell cytotoxicity (ADCC) mechanism
The dynamic changes of the immune cells, especially NK cells, T cells and monocytes, that we observed may be a reflection of the changes in the peripheral blood during a secondary DENV infection

Summary

Introduction

Antibody (Ab)-dependent enhancement (ADE) is a hypothesized mechanism of increased disease severity during secondary dengue virus (DENV) infection. Previous exposure to DENV is associated with risks of severe DENV disease[4,5,6] during a heterologous secondary infection through a hypothesized mechanism known as antibody (Ab)-dependent enhancement (ADE). Our group recently reported that non-neutralizing sera from a group of endemic subjects previously infected with DENV can bind to the surface of infected cells and can lead to rapid NK cell degranulation[10], demonstrating the existence of Abs, in the same sera, capable of triggering Ab-dependent cell cytotoxicity (ADCC). The rise of NK cells in the peripheral blood of DENV patients at the early acute stage was shown to correlate with mild disease[18], supporting a possible role of NK cells and ADCC in protection against severe diseases during natural DENV infection

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