(2017) raise another crucial question in the flavivirus field: what are the molecular and cellular mechanisms of ADE? As we wait for epidemiologic study results, animal models, in combination with main human cell culture models, will again play an important role in investigating many ADE-related questions that need to be addressed urgently. high in most areas affected by ZIKV. Considering this co-circulation of these two viruses and their close antigenic relationship at the antibody level, the severe effects of ZIKV infectioncongenital Zika syndrome and Guillain-Barre syndromemay in part be due to the influence of prior DENV antibodies during subsequent ZIKV contamination. As ZIKV spreads further into DENV-endemic regions and the Gallopamil geographic ranges of these viruses continue to merge, studies evaluating the impact of prior DENV contamination on the outcome of ZIKV contamination are urgently required. However, epidemiologic studies (both retrospective and prospective) will take several years to perform. Therefore, multiple laboratories have used cell culture models of ZIKV contamination and observed that, in vitro, DENV and ZIKV cross-reactive antibodies can reciprocally neutralize or promote ADE of ZIKV and DENV (Harrison, 2016), suggesting that pre-existing antibodies in DENV-immune individuals might contribute to ZIKV pathogenesis under certain conditions. Using a mouse model of experimental ZIKV contamination, Bardina et al. (2017) provide experimental evidence for ADE of ZIKV contamination and pathogenesis mediated by DENV-immune antibodies. Specifically, Bardina et al. (2017) harvested convalescent plasma from large numbers of DENV- or WNV-infected people (141 DENV and 146 WNV cases) and evaluated neutralization and enhancement capacities of these plasma samples against ZIKV in vitro and in vivo. In vitro studies using the human erythroleukemia cell collection K562 showed that only the highly cross-reactive DENV-immune plasma samples were capable of neutralizing ZIKV in vitro, whereas both DENV- and WNV-immune plasma enhanced ZIKV contamination, with higher ADE effects observed with DENV-immune plasma relative to WNV-immune plasma. Inhibitor- or antibody-mediated FcR blockade experiments using purified IgG from plasma and IgG-depleted plasma confirmed that this in vitro ADE induced by the DENV- and WNV-immune human plasma required the IgG-FcR conversation. To evaluate whether ADE could occur during ZIKV contamination in vivo, Bardina et al. (2017) passively transferred em Stat2 /em ?/? C57BL/6 micewhich, unlike wild-type mice, can support significant levels of ZIKV replication and manifest lethal disease due to the absence of a functional interferon responsewith pooled immune plasma from control or DENV-exposed donors and then challenged them with ZIKV. Relative to mice that received control plasma and survived the ZIKV challenge after exhibiting excess weight loss and clinical disease, mice administered a low amount of DENV-immune plasma (20 or 2 Gallopamil L/mouse) manifested greater weight loss and clinical disease and succumbed to ZIKV challenge, while those dosed with a higher amount of DENV-immune plasma (200 L/mouse) showed no disease or excess weight loss. These Gallopamil results demonstrate that this same antibodies can mediate both protection and enhancement depending on the concentration (Physique 1), in agreement with studies that Gallopamil exhibited ADE of DENV in mouse models (Balsitis et al., 2010; Zellweger et al., 2010). This Rabbit Polyclonal to ATP7B obtaining has important implications for the DENV/ZIKV pathogenesis and vaccine development fields, as it suggests that, under certain conditions, antibodies induced by prior DENV contamination or vaccination may precipitate severe ZIKV disease manifestations and vice versa (Richner et al., 2017). The precise features of the flaviviral antibody response (in terms of antibody concentration, iso-type, affinity, specificity, in vitro binding and neutralization titer, and effector functions, such as match fixation and antibody-dependent cellular cytotoxicity) that contribute to protection versus pathogenesis remain to be fully understood. Open in a separate window Physique 1 Relationship between DENV-Immune Human Plasma Level and ZIKV Disease End result in Mice By exposing the impact of DENV-immune antibodies on mediating both protection against and pathogenesis of ZIKV contamination Gallopamil in.