Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that has become a global public health threat. ZIKV infection has now been causally linked to cases of Guillain-Barre syndrome in adults and microcephaly, intrauterine growth restriction (IUGR), and spontaneous abortion in the setting of maternal infection during pregnancy. Given the recognition of this causal relationship, it is imperative to determine the mechanism(s) of maternal-fetal transmission. Insights into such mechanisms could improve our ability to reduce the burden of the effects of Zika virus infection during pregnancy. The goal of this collaborative and interactive project is to define how host defense responses can control or possibly contribute to ZIKV pathogenesis during and after pregnancy. The premise is based on the extensive newly published data showing that ZIKV infection of pregnant mice results in infection of the placenta, in utero transmission, and injury to the developing fetus. O ur central hypotheses are that maternal-fetal transmission occurs because ZIKV overcomes placental trophoblast host defenses (autophagy) (Aim 1), usurps TAM receptors to enter placental trophoblasts and endothelial cells (Aim 2); and this entire process is enhanced in flavivirus-immune individuals or animals who have sufficient levels of cross-reactive, non-neutralizing anti-ZIKV antibodies that promote ADE (Aim 3). Collectively, our efforts will be highly significant for understanding ZIKV pathogenesis. This work will provide a foundation for clinical studies that define the risks of maternal to child transmission of ZIKV, generate possible new therapeutic approaches, and determine the interaction between ZIKV and natural immunity to other flaviviruses.
Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that has become a global public health threat particularly for pregnant women as it has been causally linked to miscarriage, abnormally small fetal growth, microcephaly (small heads) and brain damage in surviving children. The goal of this proposal is to identify how ZIKV is able to cross the placental barrier to cause adverse outcomes in the baby. This work has significant clinical implications for understanding ZIKV-pathology and for developing strategies for mitigating ZIKV trafficking through the placenta and thus reducing adverse outcomes.
| Caine, Elizabeth A; Jagger, Brett W; Diamond, Michael S (2018) Animal Models of Zika Virus Infection during Pregnancy. Viruses 10: |
| Cao, Bin; Sheth, Meghal N; Mysorekar, Indira U (2018) To Zika and destroy: an antimalarial drug protects fetuses from Zika infection. Future Microbiol 13:137-139 |
| Gorman, Matthew J; Caine, Elizabeth A; Zaitsev, Konstantin et al. (2018) An Immunocompetent Mouse Model of Zika Virus Infection. Cell Host Microbe 23:672-685.e6 |
| Richner, Justin M; Diamond, Michael S (2018) Zika virus vaccines: immune response, current status, and future challenges. Curr Opin Immunol 53:130-136 |
| Platt, Derek J; Smith, Amber M; Arora, Nitin et al. (2018) Zika virus-related neurotropic flaviviruses infect human placental explants and cause fetal demise in mice. Sci Transl Med 10: |
| Allavena, Giulia; Debellis, Doriana; Marotta, Roberto et al. (2018) A broad-spectrum antibiotic, DCAP, reduces uropathogenic Escherichia coli infection and enhances vorinostat anticancer activity by modulating autophagy. Cell Death Dis 9:780 |
| Pierson, Theodore C; Diamond, Michael S (2018) The emergence of Zika virus and its new clinical syndromes. Nature 560:573-581 |
| Fowler, Angela M; Tang, William W; Young, Matthew P et al. (2018) Maternally Acquired Zika Antibodies Enhance Dengue Disease Severity in Mice. Cell Host Microbe 24:743-750.e5 |
| Richner, Justin M; Jagger, Brett W; Shan, Chao et al. (2017) Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease. Cell 170:273-283.e12 |
| Cao, Bin; Diamond, Michael S; Mysorekar, Indira U (2017) Maternal-Fetal Transmission of Zika Virus: Routes and Signals for Infection. J Interferon Cytokine Res 37:287-294 |
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