Cross-reactive antibodies facilitate innate sensing of dengue and Zika viruses
Laura K. Aisenberg, Kimberly E. Rousseau, Katherine Cascino, Guido Massaccesi, William H. Aisenberg, Wensheng Luo, Kar Muthumani, David B. Weiner, Stephen S. Whitehead, Michael A. Chattergoon, Anna P. Durbin, Andrea L. Cox
Laura K. Aisenberg, Kimberly E. Rousseau, Katherine Cascino, Guido Massaccesi, William H. Aisenberg, Wensheng Luo, Kar Muthumani, David B. Weiner, Stephen S. Whitehead, Michael A. Chattergoon, Anna P. Durbin, Andrea L. Cox
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Research Article Immunology Infectious disease

Cross-reactive antibodies facilitate innate sensing of dengue and Zika viruses

Abstract

The Aedes aegypti mosquito transmits both dengue virus (DENV) and Zika virus (ZIKV) . Individuals in endemic areas are at risk for infection with both viruses, as well as for repeated DENV infection. In the presence of anti-DENV antibodies, outcomes of secondary DENV infection range from mild to life threatening. Furthermore, the role of cross-reactive antibodies on the course of ZIKV infection remains unclear. We assessed the ability of cross-reactive DENV mAbs or polyclonal immunoglobulin isolated after DENV vaccination to upregulate type I IFN production by plasmacytoid DCs (pDCs) in response to both heterotypic DENV- and ZIKV-infected cells. We found a range in the ability of antibodies to increase pDC IFN production and a positive correlation between IFN production and the ability of an antibody to bind to the infected cell surface. Engagement of Fc receptors on the pDC and engagement of epitope on the infected cell by the Fab portion of the same antibody molecule was required to mediate increased IFN production by providing specificity to and promoting pDC sensing of DENV or ZIKV. This represents a mechanism independent of neutralization by which preexisting cross-reactive DENV antibodies could protect a subset of individuals from severe outcomes during secondary heterotypic DENV or ZIKV infection.

Authors

Laura K. Aisenberg, Kimberly E. Rousseau, Katherine Cascino, Guido Massaccesi, William H. Aisenberg, Wensheng Luo, Kar Muthumani, David B. Weiner, Stephen S. Whitehead, Michael A. Chattergoon, Anna P. Durbin, Andrea L. Cox

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Figure 5

Cross-reactive anti-DENV mAbs increase IFN production in pDC exposed to ZIKV.

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Cross-reactive anti-DENV mAbs increase IFN production in pDC exposed to ...
(A and B) Huh 7.5.1 cells were plated and infected with 0.1–1 MOI of ZIKV Nicaragua/2015 (A) or ZIKV SJRP/2015 (B) for 48 hours. Infected Huh 7.5.1 cells were replated and preincubated with anti-DENV mAbs C8, C10, 2H2, and DV87.1 for 1 hour. Primary human pDCs were added and cocultured with infected and antibody-treated Huh 7.5.1 cells for 24 hours, after which supernatants were assessed for IFN-α2a by MSD analysis. (C) Huh 7.5.1 cells were infected with ZIKV and then replated for 24 hours, at which point they were stained with DV87.1 and C10 mAbs for 1 hours at 4°C. Following surface Ab staining, the cells were fixed, permeabilized, and stained for intracellular DENV E with mouse mAb 4G2. Representative images for 4 conducted experiments are displayed (ZIKV SJRP used in displayed images). Scale bars: 10 μM. (D and E) Huh 7.5.1 cells were plated and infected with 0.1 MOI of ZIKV Nicaragua/2015 (D) or ZIKV SJRP/2015 (E) for 48 hours. Infected cells were replated and preincubated for 1 hour with the anti–ICAM-1 antibody at 0.1–5 μg/mL and C8 (D) or C10 (E) mAbs. After preincubation, primary human pDCs were isolated and cocultured with infected and antibody-treated Huh 7.5.1 cells for 24 hours, after which supernatants were assessed for IFN-α2a by MSD analysis. Each figure panel represents at least 2 independent experiments, with unique pDC donors, with n ≥ 3 per condition per experiment. Statistical significance was determined by 1-way ANOVA. ****P < 0.0001.