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Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome
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
Zika Virus: Medical Countermeasure Development Challenges
Introduction: Reports of high rates of primary microcephaly and Guillain–Barré syndrome associated with Zika virus infection in French Polynesia and Brazil have raised concerns that the virus circulating in these regions is a rapidly developing neuropathic, teratogenic, emerging infectious public health threat. There are no licensed medical countermeasures (vaccines, therapies or preventive drugs) available for Zika virus infection and disease. The Pan American Health Organization (PAHO) predicts that Zika virus will continue to spread and eventually reach all countries and territories in the Americas with endemic Aedes mosquitoes. This paper reviews the status of the Zika virus outbreak, including medical countermeasure options, with a focus on how the epidemiology, insect vectors, neuropathology, virology and immunology inform options and strategies available for medical countermeasure development and deployment. Methods: Multiple information sources were employed to support the review. These included publically available literature, patents, official communications, English and Lusophone lay press. Online surveys were distributed to physicians in the US, Mexico and Argentina and responses analyzed. Computational epitope analysis as well as infectious disease outbreak modeling and forecasting were implemented. Field observations in Brazil were compiled and interviews conducted with public health officials
Expression of ZIKV receptors in human brain and placental tissue.
<p>NA = data not available.</p
Alignment of first 130 nucleotides of 3’UTR of ZIKV, illustrating Musashi binding element (MBE) location and associated mutations over time and geographic spread.
<p>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 (<a href="http://utrsite.ba.itb.cnr.it/" target="_blank">http://utrsite.ba.itb.cnr.it/</a>).</p
States in Brazil investigating microcephaly cases for association with Zika virus infection (above), and with confirmed circulation of Zika virus (below).
<p>After [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004530#pntd.0004530.ref099" target="_blank">99</a>]. Information sources include Brazilian Health Ministry (Ministério da Saúde);WHO (World Health Organization); PAHO (Pan American Health Organization).</p
Zika virus, past and current distribution.
<p>Source: Centers for Disease Control and Prevention [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004530#pntd.0004530.ref083" target="_blank">83</a>].</p
Countries and territories with active Zika virus transmission.
<p>Countries and territories with active Zika virus transmission.</p
Projection of Zika virus infections in states with laboratory confirmation of Zika virus circulation during 2015 (18 of 27 Brazilian states or federated units).
<p>Projection of Zika virus infections in states with laboratory confirmation of Zika virus circulation during 2015 (18 of 27 Brazilian states or federated units).</p
Summary of Brazilian States (Federated units), current Zika circulation patterns, and increased incidence of primary microcephaly.
<p>Summary of Brazilian States (Federated units), current Zika circulation patterns, and increased incidence of primary microcephaly.</p