Mechanisms of Zika astrocyte infection and neuronal toxicity.

Abstract

Zika virus (ZIKV) has become an epidemic in several countries and was declared a major public health issue by the WHO. Although ZIKV infection is asymptomatic or shows mild fever-related symptoms in most people, the virus can be transmitted from a pregnant mother to the fetus, resulting in severe brain developmental abnormalities, including microcephaly. Multiple groups have identified developmental neuronal and neuronal progenitor compromise during ZIKV infection within the fetal brain, but little is known about whether ZIKV could infect human astrocytes and its effect on the developing brain. Thus, our objective was to determine astrocyte ZiKV infection in a developmental-dependent manner. We analyze infection of pure cultures of astrocytes and mixed cultures of neurons and astrocytes in response to ZIKV using plaque assays, confocal, and electron microscopy to identify infectivity, ZIKV accumulation and intracellular distribution as well as apoptosis and interorganelle dysfunction. Here, we demonstrated that ZIKV enters, infects, replicates, and accumulates in large quantities in human fetal astrocytes in a developmental-dependent manner. Astrocyte infection and intracellular viral accumulation resulted in neuronal apoptosis, and we propose astrocytes are a ZIKV reservoir during brain development. Our data identify astrocytes in different stages of development as major contributors to the devastating effects of ZIKV in the developing brain.