Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome
Authors: Klase Zachary A. , Khakhina Svetlana , Schneider Adriano De Bernardi , Callahan Michael V , Glasspool-Malone Jill , Malone Robert 
Published: April 2016

The ongoing Zika Virus epidemic in the Americas, and the observed association with both fetal abnormalities (primary microcephaly) and adult autoimmune pathology (Guillain-Barré syndrome) has brought attention to this neglected pathogen. While initial case studies generated significant interest in the Zika virus outbreak, larger prospective epidemiology and basic virology studies examining the mechanisms of Zika viral infection and associated pathophysiology are only now starting to be published. In this review, we analyze Zika fetal neuropathogenesis from a comparative pathology perspective, using the historic metaphor of “TORCH” viral pathogenesis to provide context. By drawing parallels to other viral infections of the fetus, we identify common themes and mechanisms that may illuminate the observed pathology. The existing data on the susceptibility of various cells to both Zika and other flavivirus infections are summarized. Finally, we highlight relevant aspects of the known molecular mechanisms of flavivirus replication.

Key Learning Points

Viral TORCH pathogens reveal common patterns of fetal pathophysiology and vertical transmission which are relevant to Zika Virus fetal neuropathogenesis.

The teratogenic effects of Zika Virus infection during the first trimester may involve infection of the trophoblast, viral translocation across the placenta, migration of infected cells resulting in embryonic infection, or indirect effects associated with high levels of inflammatory cytokines produced by infected placenta.

Pre-existing maternal non-neutralizing antibody to Zika virus may enhance the probability of infection or more severe disease in the fetus.

AXL has been identified as a major receptor for Zika Virus.

Zika virus activation of Toll Like Receptor 3 (TLR-3) pathways in central nervous system cells may trigger apoptosis and attenuate neurogenesis, directly contributing to fetal neuropathology.

Flaviviruses subvert host autophagy and noncoding RNA regulatory pathways.

Recognition of viral sequences by regulatory RNA binding proteins such as Musashi may have a role in Zika pathogenesis and host tissue tropism.

Evidence from other TORCH viral pathogen studies indicate multiple plausible hypotheses for transplacental infection by Zika virus during the second or third trimester, including transcytosis of non-neutralizing antibody-coated Zika virus complexes.

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