ABSTRACT
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that represents a major threat to global health. ZIKV infections in adults are generally asymptomatic or present with mild symptoms. However, recent outbreaks of ZIKV have revealed that it can cause Congenital Zika Syndrome in neonates and Guillain-Barré syndrome in adults. Currently, no ZIKV-specific vaccines or antiviral treatments are available. In this study, we tested the efficacy of convalescent plasma IgG hyperimmune product (ZIKV-IG) isolated from individuals with high neutralizing anti-ZIKV titers as a therapeutic candidate against ZIKV infection using a model of ZIKV infection in Ifnar1-/- mice. ZIKV-IG successfully protected mice from lethal ZIKV challenge. In particular, ZIKV-IG treatment at 24 hours after lethal ZIKV infection improved survival by reducing weight loss and tissue viral burden and improving clinical score. Additionally, ZIKV-IG eliminated ZIKV-induced tissue damage and inflammation in the brain and liver. These results indicate that ZIKV-IG is efficacious against ZIKV, suggesting this human polyclonal antibody is a viable candidate for further development as a treatment against human ZIKV infection.
Subject(s)
Antibodies, Neutralizing/immunology , Zika Virus Infection/immunology , Zika Virus/immunology , Animals , Antibodies, Viral/immunology , Brain/immunology , Chlorocebus aethiops , Cricetinae , Culicidae , Humans , Immunoglobulin G/immunology , Inflammation/immunology , Liver/immunology , Mice , Mice, Inbred C57BL , Vero CellsABSTRACT
Antibody (Ab)-dependent enhancement can exacerbate dengue virus (DENV) infection due to cross-reactive Abs from an initial DENV infection, facilitating replication of a second DENV. Zika virus (ZIKV) emerged in DENV-endemic areas, raising questions about whether existing immunity could affect these related flaviviruses. We show that mice born with circulating maternal Abs against ZIKV develop severe disease upon DENV infection. Compared with pups of naive mothers, those born to ZIKV-immune mice lacking type I interferon receptor in myeloid cells (LysMCre+Ifnar1fl/fl) exhibit heightened disease and viremia upon DENV infection. Passive transfer of IgG isolated from mice born to ZIKV-immune mothers resulted in increased viremia in naive recipient mice. Treatment with Abs blocking inflammatory cytokine tumor necrosis factor linked to DENV disease or Abs blocking DENV entry improved survival of DENV-infected mice born to ZIKV-immune mothers. Thus, the maternal Ab response to ZIKV infection or vaccination might predispose to severe dengue disease in infants.
Subject(s)
Antibodies, Viral/immunology , Antibody-Dependent Enhancement/immunology , Dengue Virus/immunology , Dengue/immunology , Zika Virus Infection/immunology , Zika Virus/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibody Formation , Cell Line , Cross Reactions/immunology , Culicidae , Cytokines/metabolism , Dengue Virus/pathogenicity , Disease Models, Animal , Female , Humans , Immunity , Immunoglobulin G , Male , Mice , Mice, Inbred C57BL , Myeloid Cells , Receptor, Interferon alpha-beta/metabolism , Tumor Necrosis Factor-alpha/metabolism , Viremia , Virus Internalization , Zika Virus/pathogenicity , Zika Virus Infection/virologyABSTRACT
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.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cross Reactions/immunology , Dengue Virus/immunology , Zika Virus/immunology , Animals , Decidua/pathology , Epitopes/immunology , Female , Fetus/pathology , Mice, Inbred C57BL , Phenotype , Pregnancy , Species Specificity , Spleen/immunology , Spleen/pathology , Viral Load , Zika Virus Infection/immunology , Zika Virus Infection/virologyABSTRACT
Case reports of Zika virus (ZIKV) sexual transmission and genital persistence are mounting. Venereal transmission and genital persistence threaten public health within and beyond the range of ZIKV's mosquito vectors. In this study, we administered ZIKV into the vaginas of AG129 mice and LysMCre+IFNARfl/fl C57BL/6 mice after hormonal treatments. Mice infected during estrus-like phase were resistant to vaginal infection. In contrast, when infected during diestrus-like phase, AG129 mice succumbed to infection, whereas LysMCre+IFNARfl/fl mice experienced transient illness. Patency of transgenital transmission (TGT) in diestrus-like mice was demonstrated by detection of viremia and ZIKV replication in spleen and brain, and viral RNA persisted in vaginal washes as late as 10 days post-infection. In these lethal and sublethal mouse models, this study indicates that intravaginal deposition of ZIKV can cause TGT, hormonal changes in the female reproductive tract (FRT) influence transmission, and ZIKV replication persists in the FRT for several days.
