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.Key Learning PointsViral 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.Key ReferencesAdibi JJ, Marques ET Jr, Cartus A, Beigi RH. Teratogenic effects of the Zika virus and the role of the placenta. Lancet 2016; 387: 1587–90 (Hypothesis)Adams Waldorf KM, McAdams RM. Influence of infection during pregnancy on fetal development. Reproduction. 2013 Oct 1;146(5) (Review)Hamel R, Dejarnac O, Wichit S, Ekchariyawat P, Neyret A, Luplertlop N, et al. Biology of Zika Virus Infection in Human Skin Cells. J Virol. 2015;89(17):8880–96.Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J, et al. Zika Virus Associated with Microcephaly. N Engl J Med. 2016 Feb 10.Paul LM, Carlin ER, Jenkins MM, Tan AL, Barcellona CM, Nicholson CO, Trautmann L, Michael SF, Isern S. Dengue Virus Antibodies Enhance Zika Virus Infection. bioRxiv doi: http://dx.doi.org/10.1101/050112Crow YJ, Manel N. Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol. 2015;15(7):429-40.Tonduti D, Orcesi S, Jenkinson EM, Dorboz I, Renaldo F, Panteghini C, et al. Clinical, radiological and possible pathological overlap of cystic leukoencephalopathy without megalencephaly and Aicardi-Goutieres syndrome. Eur J Paediatr Neurol. 2016.Cipolat Mis MS, Brajkovic S, Frattini E, Di Fonzo A, Corti S. Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets. Molecular and Cellular Neurosciences. 2016;72:84-90.Dang J, Tiwari SK, Lichinchi G, Qin Y, Patil VS, Eroshkin AM, Rana TM. Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3. Cell Stem Cell. 2016: 19: 1–8.Vianna FS, Schuler-Faccini L, Leite JC, de Sousa SH, da Costa LM, Dias MF, et al. Recognition of the phenotype of thalidomide embryopathy in countries endemic for leprosy: new cases and review of the main dysmorphological findings. Clin Dysmorphol. 2013;22(2):59-63.

Early epilepsy in children with Zika‐related microcephaly in a cohort in Recife, Brazil: Characteristics, electroencephalographic findings, and treatment response

“…In 2015, an outbreak of microcephaly was reported in the northeast part of Brazil. Zika virus (ZIKV) was identified as the teratogenic agent, and intrauterine ZIKV infections were observed to have repercussions for the formation and development of the fetal nervous system …”

“…Zika virus (ZIKV) was identified as the teratogenic agent, and intrauterine ZIKV infections were observed to have repercussions for the formation and development of the fetal nervous system. 1,2 To address the public health emergency of congenital Zika syndrome (CZS), the Microcephaly Epidemic Research Group (MERG; http://www.cpqam.fiocr uz.br/merg/) was formed in late 2015 and subsequently initiated three epidemiological investigations: a case-control study of microcephaly, for which the results have been published, [3][4][5] a cohort study of pregnant women with rash, 6 and a cohort of children with potential prenatal exposure to ZIKV. In addition, MERG reported on a large case series of children with microcephaly 2 and proposed an initial description of CZS.…”

Congenital Zika syndrome: Pitfalls in the placental barrier

“…The role of antibody dependent enhancement of Zika infection becomes interesting, however, in the context of vertical transmission and the congenital Zika syndrome. At approximately 16 weeks of gestation, syncytiotrophoblasts begin to express the neonatal Fc receptor that transports maternal IgG into the fetal circulation . Could non‐neutralizing IgGs bind ZIKV and co‐opt the neonatal Fc receptor to gain access to the fetal compartment?…”

“…Clinical diagnosis of microcephaly is made when a fetus or neonate has a frontal‐occipital circumference ≥ 2 standard deviations below the average for gestational age . It can be a consequence of genetic mutation, maternal malnutrition, maternal exposure to teratogenic substances (alcohol, drugs, chemicals, or ionizing radiation), or transplacental infection with TORCH pathogens ( Toxoplasma gondii , varicella zoster virus, HIV, Treponema pallidum , rubella, CMV, and herpes simplex virus) . Initially, some were skeptical that congenital ZIKV infection could have such serious clinical sequalae; however, in February 2016, ZIKV RNA was detected in the post mortem brain tissue of 2 newborns with microcephaly whose mothers presented with ZIKV infection during their first trimester of pregnancy .…”

What We Can Find Beyond the Classic Neuroimaging Findings of Congenital Zika Virus Syndrome?

“…Intrauterine ZIKV infection signs are more severe when they appear in the first and second trimesters of pregnancy, primarily in the first trimester, and range from fetal death to numerous congenital abnormalities, including redundant skin on the scalp and neck (cutis gy-rata), low birth weight, polyhydramnios, anasarca, arthrogryposis (contracture of 2 or more joints since birth), hearing loss, and ocular and CNS malformations with craniofacial disproportion [3,[12][13][14][15][16]. Among congenital manifestations, microcephaly associated with ZIKV infection has had the greatest impact.…”