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 6

Polyclonal IgG from DENV-immune individuals can enhance IFN activity of pDC exposed to DENV or ZIKV.

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Polyclonal IgG from DENV-immune individuals can enhance IFN activity of ...
(A) Huh 7.5.1 cells were infected with 0.1 MOI of DEN2-NGC for 48 hours. Polyclonal IgG isolated from DENV-vaccinated (participants VV1–3, VP1–6) or DENV-naive (participants P1, P2) participants 28 days after vaccination, with live attenuated admixture of DENV1, DENV3, and DENV4 or placebo added to culture after 48 hours. VV represents vaccinated and viremic participants, VP represents vaccinated, and protected participants, and P represents placebo-treated participants. After 1 hour of preincubation with polyclonal IgG, primary human pDCs were cocultured for 24 hours. IFN-α2a was assessed in the supernatant. The figure represents 2 independent pDC donor experiments, with n ≥ 2 per condition. (B) Infected Huh 7.5.1 cells were preincubated with the anti–ICAM-1 antibody at 2 μg/mL for 1 hour. Polyclonal IgG isolated from DENV-vaccinated (participants VV1, VP1–6) were added for 1 hour. Primary human pDCs were isolated and cocultured for 24 hours. IFN-α2a was assessed in supernatants. (C) Huh 7.5.1 cells were infected with ZIKV SJRP or ZIKV Nicaragua for 48 hours. They were then cultured with polyclonal IgG isolated from DENV-immune participants (participants VV1, VP1–4) for 1 hour and then cocultured with pDCs for 24 hours. IFN-α2a was measured in the supernatant. (B and C) A single pDC donor experiment is shown, with n ≥ 3 per condition. (D) Infected Huh 7.5.1 cells were treated with polyclonal IgG from VP3, P1, and VP4 to assess binding of polyclonal IgG to the surface of infected cells. Cells were fixed, permeabilized, and stained intracellularly with 4G2 murine anti-DENV E antibody. Representative images for 4 total experiments are displayed. Scale bars: 10 μM. Statistical significance was determined by 1-way ANOVA. ****P < 0.0001.