Abstract
As Zika virus (ZIKV) emerges into Dengue virus (DENV)-endemic areas, cases of ZIKV infection in DENV-immune pregnant women may rise. Here we show that prior DENV immunity affects maternal and fetal ZIKV infection in pregnancy using sequential DENV and ZIKV infection models. Fetuses in ZIKV-infected DENV-immune dams were normal sized, whereas fetal demise occurred in non-immune dams. Moreover, reduced ZIKV RNA is present in the placenta and fetuses of ZIKV-infected DENV-immune dams. DENV cross-reactive CD8+ T cells expand in the maternal spleen and decidua of ZIKV-infected dams, their depletion increases ZIKV infection in the placenta and fetus, and results in fetal demise. The inducement of cross-reactive CD8+ T cells via peptide immunization or adoptive transfer results in decreased ZIKV infection in the placenta. Prior DENV immunity can protect against ZIKV infection during pregnancy in mice, and CD8+ T cells are sufficient for this cross-protection. This has implications for understanding the natural history of ZIKV in DENV-endemic areas and the development of optimal ZIKV vaccines.
Highlights
As Zika virus (ZIKV) emerges into Dengue virus (DENV)-endemic areas, cases of ZIKV infection in DENV-immune pregnant women may rise
To begin to evaluate the influence of prior DENV immunity on subsequent ZIKV infection during pregnancy, we utilized our published model of sequential DENV and ZIKV infection in which mice were primed with DENV2 strain S221 for 30 days prior to ZIKV challenge[49]
DENV-immune dams treated with isotype control Ab had normal fetuses that were similar in size to uninfected, naive control dams
Summary
As Zika virus (ZIKV) emerges into Dengue virus (DENV)-endemic areas, cases of ZIKV infection in DENV-immune pregnant women may rise. One study in non-human primates showed that prior DENV exposure resulted in a reduction in the duration of ZIKV viremia in DENV-immune animals, suggesting cross-protection[50], another group reported more neutral effects of DENV immunity on ZIKV infection and disease pathogenesis[51]. In the absence of prior DENV immunity, induction by peptide immunization or adoptive transfer of cross-reactive CD8+ T cells was sufficient to protect against ZIKV infection in the setting of pregnancy. These results demonstrate that DENV/ZIKV cross-reactive CD8+ T cells can limit trans-placental transmission of ZIKV, and suggest that vaccines and therapeutics that optimize this response may minimize vertical transmission and fetal injury
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