Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/050674

Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome

Robert W Malone·Zachary Klase·Svetlana Khakhina·Michael V Callahan·Jill Glasspool-Malone·Adriano De Bernardi Schneider
View original source ↗Export metadata ↓

Abstract

The ongoing Zika Virus epidemic in the Americas, and the observed association with both fetal abnormalities (primary microcephaly) and adult autoimmune pathology (Guillain-Barre 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.\n\nKey Learning PointsO_LIViral TORCH pathogens reveal common patterns of fetal pathophysiology and vertical transmission which are relevant to Zika Virus fetal neuropathogenesis.\nC_LIO_LIThe 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.\nC_LIO_LIPre-existing maternal non-neutralizing antibody to Zika virus may enhance the probability of infection or more severe disease in the fetus.\nC_LIO_LIAXL has been identified as a major receptor for Zika Virus.\nC_LIO_LIZika 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.\nC_LIO_LIFlaviviruses subvert host autophagy and noncoding RNA regulatory pathways.\nC_LIO_LIRecognition of viral sequences by regulatory RNA binding proteins such as Musashi may have a role in Zika pathogenesis and host tissue tropism.\nC_LIO_LIEvidence 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.\nC_LI\n\nKey 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)\nAdams Waldorf KM, McAdams RM. Influence of infection during pregnancy on fetal development. Reproduction. 2013 Oct 1;146(5) (Review)\nHamel 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.\nMlakar J, Korva M, Tul N, Popovi[c] M, Polj[s]ak-Prijatelj M, Mraz J, et al. Zika Virus Associated with Microcephaly. N Engl J Med. 2016 Feb 10.\nPaul 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/10.1101/050112\nCrow YJ, Manel N. Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol. 2015;15(7):429-40.\nTonduti 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.\nCipolat 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.\nDang 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.\nVianna 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.

Source connections

Explore related subjects

Developmental BiologyPreprint

Keep this discovery

BibTeXRIS

Robert W Malone, Zachary Klase, Svetlana Khakhina, Michael V Callahan, Jill Glasspool-Malone, Adriano De Bernardi Schneider. 2016-04-29. Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome. https://doi.org/10.1101/050674

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2016

Comparative transcriptome analysis by deep RNA sequencing at early stage of skin pigmentation in goats (Capra hircus)

Although specific genes have been found to be associated with skin pigmentation, the global gene expression profile for the early stage of skin pigmentation and development in mammals is still not well understood. Here we reported a rare natural group of goat (Youzhou dark goat) featuring the dark skin of body including the visible mucous membranes, which may be an exclusive kind of large mammalian species with this special phenotype so far. In the present study, we characterized the 100-day-old fetal skin transcriptome in hyperpigmented (dark-skinned) and wild-type (white-skinned) goats using deep RNA-sequencing. A total of 923,013,870 raw reads from 6 libraries were obtained, and a large number of alternative splicing events were identified in the transcriptome of fetal skin, including the well-known melanogenic genes ASIP, TYRP1, and DCT, which were differentially expressed in the skin between the dark-skinned and white-skinned goats. Further analysis demonstrated that differential genes including ASIP, TYRP1, DCT, WNT2, RAB27A, FZD4, and CREB3L1 were significantly overrepresented in the melanogenesis pathway and several biological process associated with pigmentation. On the other hand, we identified 1616 novel transcripts in goat skin based on the characteristics of their expression level and gene composition. These novel transcripts may represent two distinct groups of nucleic acid molecules. Our findings contribute to the understanding of the characteristics of global gene expression at early stages of skin pigmentation and development, as well as describe an animal model for human diseases associated with pigmentation.

Developmental Biology↗
bioRxiv2016

A Novel function for Cactus/IκB inhibitor to promote Toll signals in the Drosophila embryo

The evolutionarily conserved Toll signaling pathway controls innate immunity across phyla and embryonic patterning in insects. In the Drosophila embryo Toll is required to establish gene expression domains along the dorsal-ventral axis. Pathway activation induces degradation of the I{kappa}B inhibitor Cactus resulting in a nuclear gradient of the NF{kappa}B effector Dorsal. Here we investigate how cactus modulates Toll signals through its effects on the Dorsal gradient and Dorsal target genes. Quantitative analysis using a series of loss and gain-of-function conditions shows that the ventral and lateral aspects of the Dorsal gradient behave differently respective to Cactus fluctuations. Unexpectedly, Cactus favors Dorsal nuclear localization required as response to high Toll signals at the ventral side of the embryo. Furthermore, N-terminal deleted Cactus mimics these effects, indicating that the ability of Cactus to favor Toll stems from mobilization of a free Cactus pool induced by the Calpain A protease. These results indicate that unexplored mechanisms are at play to ensure a correct response to high Toll signals.\n\nSummaryThe I{kappa}B protein Cactus favors high Toll signals, revealing that the ventral and lateral aspects of the Dorsal/NF{kappa}B nuclear gradient behave differently respective to Cactus concentrations in the Drosophila embryo.

Developmental Biology↗
bioRxiv2016

PCR artifact in testing for homologous recombination in genomic editing in zebrafish

We report a PCR-induced artifact in testing for homologous recombination in zebrafish. We attempted to replace the lnx2a gene with a donor cassette, mediated by a TALEN induced double stranded cut. The donor construct was flanked with homology arms of about 1 kb at the 5 and 3 ends. Injected embryos (G0) were raised and outcrossed to wild type fish. A fraction of the progeny appeared to have undergone the desired homologous recombination, as tested by PCR using primer pairs extending from genomic DNA outside the homology region to a site within the donor cassette. However, Southern blots revealed that no recombination had taken place. We conclude that recombination happened during PCR in vitro between the donor integrated elsewhere in the genome and the lnx2a locus, as suggested by earlier work [1]. We conclude that PCR alone may be insufficient to verify homologous recombination in genome editing experiments in zebrafish.

Developmental Biology↗