Differential neuronal susceptibility and apoptosis in congenital Zika virus infection

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Zika virus (ZIKV) is a flavivirus in the family Flaviviridae. It is transmitted mainly by Aedes species mosquitoes A. aegypti and A. albopictus. After initial discovery in 1947, human infections were only sporadically reported in Africa and Asia, typically accompanied by mild illness. In February 2016, as infection spread rapidly from episodic large clusters of disease in the Pacific Islands to the Americas, the World Health Organization declared ZIKV infection a Public Health Emergency of International Concern due to its association with microcephaly in the setting of congenital infection and other neurological disorders.1 There is now scientific consensus that ZIKV causes microcephaly.3 The mechanism of how congenital ZIKV infection leads to microcephaly, however, remains to be elucidated.
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.

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