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.
Highlights
Dengue is the most important mosquito-transmitted viral disease worldwide, with recent estimates indicating that 390 million infections and 96 million symptomatic dengue cases occur annually [1]
Non-neutralizing antibodies bind to dengue virus (DENV), creating immune complexes that are presented to myeloid cells or other cells with Fcγ receptors, resulting in increased production of virus, a phenomenon known as antibody-dependent enhancement (ADE) [8, 10, 11]
Our findings reveal for the first time to our knowledge that cross-reactive antibodies in human immune serum markedly exacerbate infection and spread of both DENV and Zika virus (ZIKV) in human skin, the primary site of virus transmission
Summary
Dengue is the most important mosquito-transmitted viral disease worldwide, with recent estimates indicating that 390 million infections and 96 million symptomatic dengue cases occur annually [1]. Infection by any of the 4 dengue virus (DENV) serotypes (DENV-1–4) can result in a wide spectrum of clinical manifestations, ranging from asymptomatic infection or flu-like febrile illness to life-threatening, severe dengue during primary or secondary infections [2]. The overlapping spread of ZIKV in DENV-endemic areas raises concerns that interplay between the 2 viruses could alter infection and disease dynamics [5]. This is a concern because DENV and ZIKV have a high degree of structural homology [6, 7], and immune responses raised against one virus could affect subsequent infection with the heterologous virus. Epidemiologic studies support the relationship between preexisting DENV-binding antibodies and severity of disease during natural DENV infection of humans [15, 16]
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