Zika virus-induced mechanisms of fetal harm

Abstract

Zika virus (ZIKV) is a pathogenic flavivirus that can cause significant adverse fetaloutcomes, collectively known as congenital ZIKV syndrome (CZS). However, not all pregnancies exposed to ZIKV result in an infant with apparent defects and recent research suggests that a broad range in severity of CZS can occur. During the 2013-2016 outbreak of ZIKV in the Pacific Islands and the Americas, the rate of CZS varied by geographic location, suggesting that ZIKV strains have different capacities to cause fetal harm. Ultimately, the underlying mechanisms that drive disease heterogeneity and severity are not well understood. Therefore, in this dissertation research, I investigate ZIKV strain-specific phenotypes and mechanisms of fetal harm. In Chapter 2, I characterize multiple geographically distinct ZIKV isolates from the 2015-2016 American outbreak and show that ZIKV strains vary in their capacity to cause fetal demise, intrauterine growth restriction, placental infection, and placental histopathology. These phenotypes did not correlate with the rate of fetal demise, suggesting that more subtle, underlying factors determine fetal outcome. In Chapter 3, I further investigated how ZIKV strain-dependent phenotypes arise during gestation and utilized next generation sequencing to identify potential mechanisms of fetal harm. I find that significant strain- and dose dependent activation of multiple interferon responses via retinoic-like inducible gene I (RIG-I)-like receptors in the maternal-fetal interface precedes fetal demise. Surprisingly, modest chemical inhibition of RIG-I in the maternal-fetal interface did not protect from fetal demise. In contrast, the fetal immune response was significantly associated with demise. These findings suggest that the fetal immune response is an important mediator of fetal outcome. In Chapter 4, I discuss a novel model of congenital infections—human placental organoids—that I established in the Aliota Lab. This innovative model is uniquely poised to determine how ZIKV strain-specific phenotypes translate to the human maternal-fetal interface. Further, this model can be used to identify routes of vertical transmission, which has yet to be determined for ZIKV. This dissertation identifies ZIKV strain-dependent phenotypes and mechanisms of fetal harm, and explores novel approaches to investigating congenital infections. As ZIKV continues to circulate endemically and emerge in naive populations, the studies described here inform how current and future ZIKV isolates may vary in their capacity to cause fetal harm. Further, discovery of viral RNA-driven interferon activation in the decidua, placenta, and fetus, inform our understanding of how congenital infections cause fetal harm in the absence of vertical transmission of the infectious agent.