Microcephaly and Zika virus: a clinical and epidemiological analysis of the current outbreak in Brazil

Nunes, Magda Lahorgue; Carlini, Célia R.; Marinowic, Daniel Rodrigo; Neto, Felipe Kalil; Fiori, Humberto Holmer; Scottá, Marcelo Comerlato; Zanella, Pedro Luis Ávila; Soder, Ricardo Bernardi; Costa, Jaderson Costa da

doi:10.1016/j.jped.2016.02.009

Cited by 121 publications

(110 citation statements)

References 63 publications

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“…This may have resulted due to differences in experimental design, cultured cells employed (induced pluripotent stem cells derived from human skin cells versus human fetal brain progenitor neurons derived from childhood neuronal crest cells (neuroblastoma; 30). Also we used the ZIKV strain that is genetically similar to the current Brazilian strain of ZIKV (MR766 versus PRVABC59; Zhu et al, 2016, Nunes et al, 2016). Other morphological changes associated with ZIKV infection included syncytia and giant cell formation, which generally results due to the expression of viral fusion proteins (Lee and Bowden, 2000), and central chromatolysis, wherein chromatin and cell nuclei were dislocated to the cell's periphery, indicating general injury.…”

Section: Discussionmentioning

confidence: 99%

Infectivity of Immature Neurons to Zika Virus: A Link to Congenital Zika Syndrome

et al. 2016

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BackgroundEpidemiological data strongly suggest that microcephaly cases in Brazil are associated with the ongoing epidemic of Zika virus (ZIKV). In order to further solidify the possible link, we investigated the infectivity of ZIKV using various neuroblastoma (NB) cell lines.MethodsSix undifferentiated, two terminally differentiated and two retinoic acid (RA) –induced, partially differentiated cell lines were exposed to ZIKV strain PRVABC59, which is genetically similar to the French Polynesia strain, with 97–100% genetic homology to the current ZIKV strain found in Brazil. All infections were confirmed by real-time PCR (RT-qPCR), immunofluorescence assay (IFA) probing with anti-flavivirus E antibody, and evaluation of cytopathic effects.FindingsZIKV infected all six undifferentiated NB cell lines. In five out of six NB cell lines, between 90 and 70% cells were positive by IFA whereas for one cell line, CCL-127, ~ 80% of cells were positive for ZIKV as determined by IFA but showed persistent infection. Two differentiated cell lines, JFEN and T-268, were highly resistant to ZIKV with < 1% of the cells being susceptible, as determined by IFA and confirmed by qRT-PCR. Two retinoic acid (RA)-induced NB partially differentiated cell lines showed no difference in permissiveness as compared to their undifferentiated mother cell lines.InterpretationThese findings strengthen the reported association between high incidences of microcephaly and ZIKV infection in newborns in Brazil. Our results suggest that the undifferentiated neurons are highly permissive to ZIKV infection, as one would expect during the early stages of neurogenesis in fetal brains; whereas differentiated neurons, representative of adult brain neurons, are relatively resistant to the virus, which explains the rare occurrence of neurological complications in adults infected with ZIKV. Our studies confirm the neurotropism of the ZIKV strain closely related to the current epidemic in Latin America.

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Section: Discussionmentioning

confidence: 99%

Infectivity of Immature Neurons to Zika Virus: A Link to Congenital Zika Syndrome

et al. 2016

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“…It has been demonstrated that ZIKV can infect human induced pluripotent stem cell–derived neural progenitor cells as well as human neurospheres and brain organoids in vitro, resulting in dysregulation of cell cycle–related pathways and increased cell death [33–36]. While the etiology remains unconfirmed, there appears to be a shift in the spectrum and incidence of birth defects between the latter stage of the French Polynesian outbreak [37] and what is now being observed in Recife, Rio, and throughout northern Brazil and surrounding regions [38,39]. In general, the combination of epidemiologic association and experimental research results strongly support a causal relationship between intrauterine ZIKV infection and fetal primary microcephaly.…”

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Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome

et al. 2016

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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.

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“…The six miRNAs – miR-627–5 , miR-4646 , miR-1304 , miR-6771 , miR-4528 , and miR-3198 – shared high degrees of mutual homologies to the ZIKV genome and the 12 MCPH genes (Table 1 and Figure 1). In all cases, these miRNAs shared 100% identity at the seed sequences (3ʹ-2–8 base pairs) and between 75–100% homologies at the genetic level, suggesting that the genetic targets we identified most likely play a significant role in inducing MCPH [32]. To our knowledge, this is the first report of the comparative analyses of mutually homologous miRNAs in ZIKV and MCPH genes.…”

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confidence: 97%

“…miRNAs are critical regulators of gene expression that utilize sequence complementarity to bind to and modulate the stability or translation efficiency of target mRNAs. In the case of GBV-C, a nonpathogenic flavivirus, profound modulations of miRNAs have been reported [32]. Accumulating data suggest that miRNAs regulate a wide variety of molecular mechanisms in host cells during viral infections [31,32].…”

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confidence: 99%

“…The E protein, which is ∼53 kDa, is glycosylated. Since the E protein is the main viral antigenic determinant, with membrane binding and fusion capacity when the virus enters the infected cell, any modulation by miR-1304 would be an important factor to investigate [16,32]. Upon release of viral RNA into the cytoplasm of infected cells, it is replicated and translated by the cellular machinery, leading to the formation of new viral particles.…”

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Computational identification of mutually homologous Zika virus miRNAs that target microcephaly genes

McLean

Bhattarai

Hughes

et al. 2017

Libyan Journal of Medicine

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Background Zika virus (ZIKV) has been associated with a variety of neuropathologies, including microcephaly. We hypothesize that ZIKV genes activate host microRNAs (miRNAs) causing dysfunctional development of human fetal brains. Objectives/methods A bioinformatics search for miRNA genome-wide binding sites in the prototypic ZIKV (strain MR766) was undertaken to hunt for miRNAs with significant similarities with MCPH genetic sequences responsible for inducing MCHP in human fetal brains. Results Six ZIKV miRNAs were found to share mutual homology with 12 MCPH genetic sequences responsible for inducing MCPH. Noteworthy was miR-1304, which expressed 100% identity to six different MCPH genes. Conclusions We suggest that following infection of fetal neurons ZIKV may modulate the action of various miRNAs, and miR-1304 in particular, resulting in microcephaly.

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Microcephaly and Zika virus: a clinical and epidemiological analysis of the current outbreak in Brazil

Cited by 121 publications

References 63 publications

Infectivity of Immature Neurons to Zika Virus: A Link to Congenital Zika Syndrome

Infectivity of Immature Neurons to Zika Virus: A Link to Congenital Zika Syndrome

Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome

Computational identification of mutually homologous Zika virus miRNAs that target microcephaly genes

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