Activation and Inhibition of Autophagy and the Lysosome: Potential Therapeutic Avenues for Prenatal Zika Virus Infection

Abstract

Zika virus (ZIKV), a mosquito-borne flavivirus, has been found in 87 countries and territories. Global outbreaks peaked in 2016. Prenatal Zika virus infection was found to be associated with microcephaly, arthrogryposis, intracranial calcifications, fetal growth restriction, and fetal demise. The most severely affected children were diagnosed with congenital Zika syndrome, which impacts thousands worldwide. With no approved treatment or preventative measures for Zika virus, future viral outbreaks have the potential to cause epidemic levels of prenatal brain injury, as seen over the past 70 years. Therefore, there is a great need for a reliable and clinically translational experimental system that mimics the human condition of prenatal Zika virus infection. To this end, we developed a novel, humanized, immunocompetent preclinical system of virally induced brain injury from prenatal Zika virus infection, which ranges from mild to severe. Here, we describe the extent to which this system mirrors the human phenotypic spectrum. Using our thorough preclinical system, we find that prenatal Zika virus infection of mice impacts survival rate, anthropometric measurements, tissue formation, and neurological outcomes, all of which are typically affected by prenatal infection. Current and future applications include the identification of genetic or environmental modifiers of brain injury, molecular or mechanistic studies of pathogenesis, and preclinical evaluation of future therapies.