Using Precision Therapies to Protect the Developing Brain from Viral Infection and Injury

Abstract

Prenatal viral infections can cause severe damage to the developing brain. Among the most threatening, Zika virus can cause microcephaly, ocular abnormalities, seizures, and fetal demise. Currently, there is no prenatal standard of care or treatment for Zika infection. Preliminary data and existing literature suggest that autophagy and the lysosome are crucial modifiers of injury and, thus, potential avenues for therapy. In this work, we will determine the effect of three drugs that manipulate autophagy in unique ways on the outcomes of prenatal viral infection; Trehalose, a lysosomal flux activator; Metformin, which induces AMPK signaling; and PD146176, an activator of the cells’ degradative machinery independent of mTORC1 through selective 12/15-lipoxygenase inhibition. Chloroquine, a lysosomal inhibitor known to mitigate the adverse outcomes of prenatal viral infections, serves as our positive control. Here, we infect humanized (hSTAT2 KI/KI), immunocompetent mice at a time point analogous to the first trimester in humans and perform comprehensive prenatal and postnatal analysis. Thus far, we have found that Metformin significantly rescues postnatal survival. In addition to identifying prenatal therapies, future work may also include testing postnatal treatments to account for infected infants not identified prenatally. These findings may also be clinically translatable for other prenatally transmitted viruses, such as Oropouche and cytomegalovirus.