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 4

Reciprocal immune enhancement of DENV and ZIKV infection in human skin.

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Reciprocal immune enhancement of DENV and ZIKV infection in human skin. ...
(A) Representative images showing NS3 (green) expression after inoculation with 103 FFU of ZIKV in human skin pretreated with DENV-3 immune sera or naive sera. Scale bar: 50 μm. (B) Quantification of ZIKV infection in the epidermis and dermis of skin inoculated in the presence of DENV-3 immune sera or naive sera. *P < 0.05 (Mann-Whitney U test) comparing DENV-3 immune sera with naive sera. (C) Quantification of area of cells, area of infected cells, and percentage of infected cells for each cell type (macrophages, dermal DCs, and LCs) in the dermis after inoculation with ZIKV in skin pretreated with 1:40 dilution of DENV-3 immune sera or naive sera. Each symbol is an individual donor and horizontal line is the mean. *P < 0.05 (Mann-Whitney U test). (D) Quantification of ZIKV and DENV-2 infection in the epidermis and dermis of skin inoculated in the presence of ZIKV immune sera or naive sera. *P < 0.05 (Mann-Whitney U test) comparing ZIKV immune sera with naive sera. Data in B and D are from 4 skin donors expressed as mean ± SEM. (E) Representative images showing NS3 (green) expression after inoculation with 103 FFU of DENV-2 or ZIKV in human skin pretreated with ZIKV immune sera. Scale bar: 50 μm. Blue staining in A and E represents nuclei and dotted lines indicate epidermal-dermal junction. (F) Fold increase (power of enhancement) in the density of DENV-2– and ZIKV-infected cells in the presence of DENV-3 immune sera relative to naive sera and DENV-2–infected cells in the presence of ZIKV immune sera relative to naive sera at peak enhancement. Data are from 4 skin donors expressed as mean ± SEM.