Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome

Abstract

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.

Fig 1. Projected teratogenic impact of maternal ZIKV infection on 2017–2018 birth cohort, Puerto Rico.

For illustration purposes, the potential impact of unencumbered ZIKV spread through Puerto Rico on the cumulative one-year incidence of ZIKV-associated birth defects has been estimated and graphically summarized. Birth defect rate is based on preliminary data involving defects visible by in utero ultrasound examination from Brazilian (Rio) prospective pregnancy cohort study [38]. Final seroconversion rate of 70% is based on seroconversion observed with prior island outbreaks in Yap and French Polynesia [51,52]. Annual birth cohort for Puerto Rico is approximated as 36,000 infants, a number which presumes that the incidence of pregnancy is not impacted by anticipated risk of ZIKV infection or public health policy recommendations. Total birth defect rate associated with intrauterine ZIKV infection in Northern and Central Brazil is currently not determined and may exceed 30% of all Zika-infected pregnancies. WHO estimates of the US costs of caring for a single child with microcephaly are as high as $10 million [54]. 75 billion US dollars = US$75,000,000,000.

Fig 2. Alignment of first 130 nucleotides of 3’UTR of ZIKV, illustrating Musashi binding element (MBE) location and associated mutations over time and geographic spread.

Sequences shown are the only ones that are unique for country and/or sequence; duplicates of the same country were discarded. Alignment was performed using the MAFFT multiple sequence alignment program for unix-like operating systems. Visualization was performed using Geneious. There is presence of stem-loop I (SL I) and stem-loop II (SL II) on those sequences, with SL II being partially shown. There is also presence of MBE on SL II, with two SNPs on African sequences, which could potentially change the RNA structure and availability of the element. SL I and SL II were annotated from Zhu Z. et al. MBE was annotated using the UTRscan tool of UTRSite (http://utrsite.ba.itb.cnr.it/).