Reciprocal immune enhancement of dengue and Zika virus infection in human skin
Priscila M. S. Castanha, Geza Erdos, Simon C. Watkins, Louis D. Falo Jr., Ernesto T. A. Marques, Simon M. Barratt-Boyes
Priscila M. S. Castanha, Geza Erdos, Simon C. Watkins, Louis D. Falo Jr., Ernesto T. A. Marques, Simon M. Barratt-Boyes
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Research Article Immunology Infectious disease

Reciprocal immune enhancement of dengue and Zika virus infection in human skin

Abstract

Dengue virus (DENV) and Zika virus (ZIKV) are closely related mosquito-borne flaviviruses that co-circulate in tropical regions and constitute major threats to global human health. Whether preexisting immunity to one virus affects disease caused by the other during primary or secondary infections is unknown but is critical in preparing for future outbreaks and predicting vaccine safety. Using a human skin explant model, we show that DENV-3 immune sera increased recruitment and infection of Langerhans cells, macrophages, and dermal dendritic cells following inoculation with DENV-2 or ZIKV. Similarly, ZIKV immune sera enhanced infection with DENV-2. Immune sera increased migration of infected Langerhans cells to the dermis and emigration of infected cells out of skin. Heterotypic immune sera increased viral RNA in the dermis almost 10-fold and reduced the amount of virus required to infect a majority of myeloid cells by 100- to 1000-fold. Enhancement was associated with cross-reactive IgG and induction of IL-10 expression and was mediated by both CD32 and CD64 Fcγ receptors. These findings reveal that preexisting heterotypic immunity greatly enhances DENV and ZIKV infection, replication, and spread in human skin. This relevant tissue model will be valuable in assessing the efficacy and risk of dengue and Zika vaccines in humans.

Authors

Priscila M. S. Castanha, Geza Erdos, Simon C. Watkins, Louis D. Falo Jr., Ernesto T. A. Marques, Simon M. Barratt-Boyes

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Figure 5

Cross-reactive antibodies in immune sera mediate enhancement through CD32 and CD64 Fcγ receptor engagement and IL-10 expression.

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Cross-reactive antibodies in immune sera mediate enhancement through CD3...
(A) Binding IgG properties of DENV-3 and ZIKV immune serum to DENV-2, DENV-3, and ZIKV particles. Data are from 4 skin donors expressed as mean ± SEM. Dotted line represents optical density value of the negative control plus 3 times the standard deviation. (B) Percentage of binding IgG in immune sera that binds to homologous virus or cross-reacts with heterologous virus, calculated as follows: percentage of cross-reactive binding IgG = (endpoint titer against heterologous virus/endpoint titer against homologous virus) × 100. Percentage of type-specific binding IgG = 100 − percentage of cross-reactive IgG. (C) Expression of innate immune genes determined by real-time PCR in whole digests of mock-infected skin or skin infected with DENV-2 in the presence of DENV-3 immune sera or naive sera. Changes in expression of genes are presented as a heatmap of log2-transformed expression ratios relative to control skin before infection. (D) Quantification of the density of NS3-expressing cells in the dermis after inoculation with 103 FFU of DENV-2 in skin pretreated with neutralizing antibodies against CD32 or CD64 combined with a 1:40 dilution of DENV-3 immune sera or naive sera. (E) Number of migrated cells collected from medium per square inch of skin treated as in D. (F) Quantification of the density of macrophages, dermal DCs, and LCs in the dermis after inoculation with DENV-2 in skin treated as in D. (G) Quantification of the area of infected macrophages, dermal DCs, and LCs in the dermis after inoculation with DENV-2 in skin treated as in D. Data are from 4 skin donors expressed as mean ± SEM. *P < 0.05, and **P < 0.05 determined by Kruskal-Wallis 1-way ANOVA followed by Dunn’s multiple-comparisons test.