Differential neuronal susceptibility and apoptosis in congenital Zika virus infection
Recent studies in human induced pluripotent stem cell–derived neural progenitor and organoid culture systems have provided novel insight into the pathogenesis of ZIKV‐related microcephaly. These studies show that ZIKV preferentially infects neural progenitor cells (NPCs), attenuates cell growth, and induces cell death.4 These findings have also been observed in mouse models, which further demonstrated the development of microcephaly in infected fetal mice.7 Although cell culture and animal models are valuable resources for ZIKV studies, they may not fully recapitulate human disease, due to the inherently artificial components of the experimental setup, including required manipulation of murine host immune responses for infection. Therefore, human studies remain critical for investigating virus–host interactions and phenotypic variability of ZIKV‐induced neurologic injury.
Several postmortem studies of ZIKV‐infected fetuses and infants have been published since the inception of the ZIKV outbreak. They have demonstrated a spectrum of gross and microscopic brain anomalies including microcephaly, lissencephaly, hydrocephalus, cerebellar hypoplasia, intracranial calcifications, brain parenchyma necrosis, and inflammatory infiltrates.10 Of note, the majority of the cases were fetuses examined in the third trimester of pregnancy (after antecedent infection earlier in the pregnancy), at a point when neurogenesis has been largely completed. This may explain why attenuated growth or apoptosis of NPCs, the key finding of cell culture and animal studies to date, has not been observed in infected human fetuses. To investigate whether findings in cell culture and animal model systems are representative of pathogenesis in human fetal brain tissue, we performed immunofluorescence analysis on brain tissue from a 20‐week gestation fetus with confirmed ZIKV infection and retarded brain growth.10 Compared with other postmortem studies,11 our case is unique in that neurogenesis remains ongoing and robust at this gestational age.