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 4

Antibody-mediated upregulation of pDC sensing and IFN production requires Fc engagement of FcR2a on pDCs.

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Antibody-mediated upregulation of pDC sensing and IFN production require...
Huh 7.5.1 cells were infected with DENV at 0.1 MOI for 48 hours. (A) Infected Huh 7.5.1 were treated with DV87.1 or LALA DV87.1 antibody for 1 hour, followed by pDC coculture for 24 hours. (B) Infected hepatoma cells were cultured with DV87.1 for 1 hour, while pDCs were treated with FcBlock or anti-FcγR2a antibody for 1 hour. pDCs were then cocultured with Huh 7.5.1 for 24 hours. (C and D) Huh 7.5.1 were incubated with anti–ICAM-1 antibody at 2 μg/mL (C) or anti–αL integrin antibody at 0.1 μg/mL with or without DV87.1 (0.1 μg/mL or 1 μg/mL) or LALA DV87.1 (0.1 μg/mL or 1 μg/mL) (D). Afterward, they were cocultured with primary human pDCs for 24 hours. (E) Huh 7.5.1 cells were treated with anti–ICAM-1 blocking antibody at 2 μg/mL with 0.1 μg/mL or 1 μg/mL of DV87.1, while pDCs were treated with anti-FcγR2a blocking antibody at 10 μg/mL. (F) Infected Huh 7.5.1 cells were incubated with anti–ICAM-1 antibody at 2 μg/mL with 1 μg/mL of DV87.1 and increasing amounts of LALA DV87.1 (0.1 μg/mL or 10 μg/mL) for 1 hour; they were then cocultured with pDCs. All supernatants were collected and assessed for IFN-α2a by MSD analysis. Each panel represents 15 (A) and 3 (2–3 per condition) (B) independent experiments with unique pDC donors, with n ≥ 3 per condition per experiment. (C, E, and F) At least 2 independent experiments are shown, with unique pDC donors, and n ≥ 3 per condition per experiment. (D) A single pDC donor experiment is shown, with n ≥ 3 per condition. Statistical significance was determined by 1-way ANOVA. *P < 0.05, **P < 0.01, ****P < 0.0001.