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Zika Retards Growth of Human Cortical Neural Progenitors - Cell Stem Cell

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Zika virus (ZIKV), a mosquito-borne flavivirus, is now reported to be circulating in 26 countries and territories in Latin America and the Caribbean (Petersen et al., 2016). While infected individuals can often be asymptomatic or have only mild symptoms, of mounting concern are reports linking ZIKV infection to fetal and newborn microcephaly and serious neurological complications, such as Guillain-Barré syndrome (Petersen et al., 2016). The World Health Organization declared a Public Health Emergency of International Concern on February 1 of 2016 (Heymann et al., 2016). ZIKV infects human skin cells, consistent with its major transmission route (Hamel et al., 2015). ZIKV was detected in the amniotic fluid of two pregnant women whose fetuses had been diagnosed with microcephaly (Calvet et al., 2016), suggesting that ZIKV can cross the placental barrier. ZIKV was also found in microcephalic fetal brain tissue (Mlakar et al., 2016). Because so little is known about direct cell targets and mechanisms of ZIKV, and because access to fetal human brain tissue is limited, there is an urgent need to develop a new strategy to determine whether there is a causal relationship between ZIKV infection and microcephaly. Here we used human induced pluripotent stem cells (hiPSCs) as an in vitro model to investigate whether ZIKV directly infects human neural cells and the nature of its impact.

We obtained a ZIKV stock from the infected rhesus Macaca cell line LLC-MK2. We passaged the virus in the mosquito C6/C36 cell line and titered collected ZIKV on Vero cells, an interferon-deficient monkey cell line commonly used to titer viruses. Sequences of multiple RT-PCR fragments generated from this stock (Figure S1A) matched the sequence of MR766, the original ZIKV strain that likely passed from an infected rhesus monkey to mosquitos (Dick et al., 1952). We first tested several human cell lines and found varying levels of susceptibility to ZIKV infection (Table S1). Notably, the human embryonic kidney cell line HEK293T showed low permissiveness for ZIKV infection (Figure S1C).

To identify direct target cells of ZIKV in the human neural lineage, we used a highly efficient protocol to differentiate hiPSCs into forebrain-specific human neural progenitor cells (hNPCs), which can be further differentiated into cortical neurons (Wen et al., 2014). The titer of ZIKV in the infected humans is currently unknown. We performed infections at a low multiplicity of infection (MOI < 0.1) and the medium containing virus inoculum was removed after a 2 hr incubation period. Infection rates were then quantified 56 hr later with RT-PCR using MR766-specific primers (Figure S1A) and with immunocytochemistry using an anti-ZIKV envelope antibody (Figures 1A and 1B ). The hNPCs were readily infected by ZIKV in vitro, with the infection spreading to 65%–90% of the cells within 3 days of inoculation (Figures 1A and 1C). Quantitative analysis showed similar results for hNPCs derived from hiPSC lines of two different subjects (Figure 1C). As a control, we also exposed human embryonic stem cells (hESCs), hiPSCs, and immature cortical neurons to ZIKV under the same conditions. hESCs and hiPSCs could also be infected by ZIKV, but the infection was limited to a few cells at the colony edge with reduced expression of the pluripotent marker NANOG (Figures 1C and S1D; Table S1). Immature neurons differentiated from hNPCs also exhibited lower levels of infection under our conditions (Figures 1B and 1C). Together, these results establish that hNPCs, a constitutive population of the developing embryonic brain, are a direct cell target of ZIKV.

 

ZIKV envelope immunostaining exhibited the characteristic intracellular “virus factory” pattern of flaviviruses (Romero-Brey and Bartenschlager, 2014) (Figure 1A). We therefore tested infectivity using supernatant from infected hNPCs and observed robust infection of Vero cells (Figure 1D), indicating that productive infection of hNPCs leads to efficient secretion of infectious ZIKV particles.

We next determined the potential impact of ZIKV infection on hNPCs. We found a 29.9% ± 6.6% reduction in the total number of viable cells 66–72 hr after ZIKV infection, as compared to the mock infection (n = 3). Interestingly, ZIKV infection led to significantly higher caspase-3 activation in hNPCs 3 days after infection, as compared to the mock infection, suggesting increased cell death (Figures 2A and 2B ). Furthermore, analysis of DNA content by flow cytometry suggested cell-cycle perturbation of infected hNPCs (Figures 2C and S2A). Therefore, ZIKV infection of hNPCs leads to attenuated growth of this cell population that is due, at least partly, to both increased cell death and cell-cycle dysregulation.

 

To investigate the impact of ZIKV infection on hNPCs at the molecular level, we employed global transcriptome analyses (RNA-seq). Our genome-wide analyses identified a large number of differentially expressed genes upon viral infection (Figure S2B and Table S2). Gene Ontology analyses revealed a particular enrichment of downregulated genes in cell-cycle-related pathways (Figure 2D), which is consistent with our flow cytometry findings (Figure 2C). Upregulated genes were primarily enriched in transcription, protein transport, and catabolic processes (Figure 2E). Consistent with increased caspase-3 activation observed by immunocytochemistry (Figures 2A and 2B), RNA-seq analysis revealed upregulation of genes, including caspase-3, involved in the regulation of the apoptotic pathway (Figure 2E). These global transcriptome datasets not only support our cell biology findings but also provide a valuable resource for the field.

It is not known whether specific strains of ZIKV circulating in geographically diverse parts of the world differ in their ability to impact neural development, and the stain we used had been discovered prior to the current reports of a potential epidemiologic link between ZIKV and microcephaly. Nevertheless, our results clearly demonstrate that ZIKV can directly infect hNPCs in vitro with high efficiency and that infection of hNPCs leads to attenuated population growth through virally induced caspase-3-mediated apoptosis and cell-cycle dysregulation. Infected hNPCs also release infectious viral particles, which presents a significant clinical challenge for developing effective therapeutics to arrest or block the impact of infection. Future studies using the hiPSC/hNPC model can determine whether various ZIKV strains impact hNPCs differently and, conversely, whether a single ZIKV strain differentially affects hNPCs from hiPSCs of various human populations.

Flaviviruses tend to have broad cellular tropisms and multiple factors contribute to pathogenic outcomes, including specific cellular response and tissue accessibility. Dengue virus infects cells of several lineages and hematopoietic cells play an essential role in the associated pathogenesis (Pham et al., 2012). West Nile virus infects epithelial cells of multiple tissues and can be neuroinvasive (Suthar et al., 2013). We note that ZIKV also infects other human cell types, including skin cells and fibroblasts (Hamel et al., 2015), and it remains unknown how ZIKV may gain access to the fetal brain (Mlakar et al., 2016). The capacity of ZIKV to infect hNPCs and attenuate their growth underscores the urgent need for more research into the role of these cells in putative ZIKV-related neuropathology. The finding that ZIKV also infects immature neurons raises critical questions about pathological effects on neurons and other neural cell types in the brain, as well as potential long-term consequences. Intriguingly, an early animal study showed ZIKV infection of neurons and astrocytes in mice and observed enlarged astrocytes (Bell et al., 1971). Our study also raises the question of whether ZIKV infects neural stem cells in adult humans (Bond et al., 2015).

In summary, our results fill a major gap in our knowledge about ZIKV biology and serve as an entry point to establish a mechanistic link between ZIKV and microcephaly. Our study also provides a tractable experimental system for modeling the impact of ZIKV on neural development and for investigating underlying cellular and molecular mechanisms. Of equal importance, our hNPC model and robust cellular phenotype comprise a readily scalable platform for high-throughput screens to prevent ZIKV infection of hNPCs and to ameliorate its pathological effects during neural development.

Author Contributions

H.T., H.S., and G.-l.M. conceived of the research, designed the study, and wrote the manuscript. C.H., S.C.O., Z.W., and X.Q. performed experiments, analyzed data, and contributed equally to this study. Y.L., B.Y., J.S., F.Z., and P.J. performed RNA-seq analysis, and E.M.L., K.M.C., and R.A.D. contributed to additional data collection. All authors commented on the manuscript.

Acknowledgments

We thank Yichen Cheng, Taylor Lee, and Jianshe Lang of the Tang laboratory, Lihong Liu and Yuan Cai of the Ming and Song laboratories, Luoxiu Huang of the Jin laboratory for technical assistance, Zhiheng Xu and additional laboratory members for suggestions, and Timothy Megraw for assistance with confocal imaging. H.T. thanks the College of Arts and Sciences and the Department of Biological Science at Florida State University for seed funding. This work was partially supported by NIH (AI119530/AI111250 to H.T., NS047344 to H.S., NS048271/NS095348 to G-l.M., and NS051630/NS079625/MH102690 to P.J.), MSCRF (to H.S.), and start-up funding (to H.S.).

Accession Numbers

The accession number for RNA-seq data reported in this paper is GEO:GSE78711.

Supplemental Information

 

Document S1. Figures S1 and S2, Table S1, and Supplemental Experimental Procedures
Table S2. Differential Gene Expression between ZIKV-Infected and Mock-Infected hNPCs, Related to Figure 2
(A) Sequencing information. (B) List of downregulated genes. (C) List of upregulated genes.
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References

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Title

Source

Bell, T.M., Field, E.J., and Narang, H.K.Zika virus infection of the central nervous system of mice.
Bond, A.M., Ming, G.L., and Song, H.Adult mammalian neural stem cells and neurogenesis: Five decades later.
Calvet, G., Aguiar, R.S., Melo, A.S., Sampaio, S.A., de Filippis, I., Fabri, A., Araujo, E.S., de Sequeira, P.C., de Mendonça, M.C., de Oliveira, L. et al.Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study.
Dick, G.W., Kitchen, S.F., and Haddow, A.J.Zika virus. I. Isolations and serological specificity.Trans. R. Soc. Trop. Med. Hyg.1952; 46: 509–520
Hamel, R., Dejarnac, O., Wichit, S., Ekchariyawat, P., Neyret, A., Luplertlop, N., Perera-Lecoin, M., Surasombatpattana, P., Talignani, L., Thomas, F. et al.Biology of Zika virus infection in human skin cells.
Heymann, D.L., Hodgson, A., Sall, A.A., Freedman, D.O., Staples, J.E., Althabe, F., Baruah, K., Mahmud, G., Kandun, N., Vasconcelos, P.F. et al.Zika virus and microcephaly: why is this situation a PHEIC?.
Mlakar, J., Korva, M., Tul, N., Popović, M., Poljšak-Prijatelj, M., Mraz, J., Kolenc, M., Resman Rus, K., Vesnaver Vipotnik, T., Fabjan Vodušek, V. et al.Zika virus associated with microcephaly.
Petersen, E., Wilson, M.E., Touch, S., McCloskey, B., Mwaba, P., Bates, M., Dar, O., Mattes, F., Kidd, M., Ippolito, G. et al.Rapid spread of Zika virus in the Americas - Implications for public health preparedness for mass gatherings at the 2016 Brazil Olympic Games.
Pham, A.M., Langlois, R.A., and TenOever, B.R.Replication in cells of hematopoietic origin is necessary for Dengue virus dissemination.
Romero-Brey, I. and Bartenschlager, R.Membranous replication factories induced by plus-strand RNA viruses.
Suthar, M.S., Diamond, M.S., and Gale, M. Jr.West Nile virus infection and immunity.
Wen, Z., Nguyen, H.N., Guo, Z., Lalli, M.A., Wang, X., Su, Y., Kim, N.S., Yoon, K.J., Shin, J., Zhang, C. et al.Synaptic dysregulation in a human iPS cell model of mental disorders.
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LAB-GROWN BRAIN BALLS STRENGTHEN ZIKA’S LINK TO MICROCEPHALY

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THE SUSPECTED LINK between Zika and microcephaly is looking stronger and stronger.

At first, you may recall, the link was pure correlation: Brazil saw a huge uptick this fall in cases of microcephaly, a condition where babies are born with brains that are too small, at the same time Zika spread through the country. In the past few months, scientists have found the virus in the placenta, amniotic fluid, and—most tellingly—brain tissue of microcephalic fetuses.

Now two new papers show that Zika kills developing brain tissue culture in a dish. Those results don’t completely solidify the link between the virus and birth defects, but public health officials aren’t taking any chances. “The association is strong enough that we need to assume that it is true until we show that it’s not,” says Amelia Pinto, an immunologist at St. Louis University, who was not involved in either study.

In one paper, a team based at the Federal University of Rio Janeiro grew neural stem cells into tiny little balls of brain tissue called cerebral organoids. These aren’t as complex as full brains, but they give scientists a window into brain development, namely how an undifferentiated mass of stem cells turns into the different tissues of the brain. And with Zika, it didn’t look good. In the eleven days after the organoids were infected with Zika, they grew 40 percent less than the healthy ones. The paper was uploaded to the preprint archive PeerJ, though it has not been peer reviewed or published in a journal yet.

In a second paper published today in the journal Cell Stem Cell, a Johns Hopkins University group didn’t grow brain balls. Instead, they took stem cells and turned them into a specific type of human neural progenitor cells, which are the precursor to cortical neurons. They found that these neural progenitor cells were especially vulnerable to Zika. The virus had marginal effects on the cells they grew from (stem cells) or the cells they grew into (cortical neurons), but it killed nearly a third of the human neural progenitor cells.

What’s going on with the neural progenitor cells? Zika infection seemed to scramble normal gene expression in those cells, tamping down genes that help them grow into neurons and turning on genes for cell death. The group is now continuing this work in cerebral organoids says Guo-Li Ming, a neuroscientist at Johns Hopkins who led this study.

As with any cell culture experiment, these papers have limitations. One caveat is the type of stem cells both groups used. They started with fully fledged adult cells that were “backwards aged” into stem cells and then chemically coaxed into neural stem cells. That’s not how brains develop in fetuses. But using actual human fetal brain tissue is very difficult. (See the whole controversy over Planned Parenthood’s role in providing fetal tissue last year.)

More obviously, though, cells in a dish are not developing fetuses. Scientists hope to use animal models to piece together the complete story. Pinto is one of multiple researchers now using immunocompromised mice as a model for Zika infection. She’s especially interested in how the immune system’s inflammatory response to the virus may also might play a role in the brain defects. The story might get more complicated before it gets untangled.

http://www.wired.com/2016/03/lab-grown-brain-balls-strengthen-zikas-link-microcephaly/

 

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Zika caught 'killing' brain cells

By James GallagherHealth editor, BBC News website
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Baby with microcephalyImage copyrightGetty Images

Zika virus kills the type of tissue found in the developing brain, researchers have shown.

It was able to destroy or disrupt the growth of neural progenitor cells, which build the brain and nervous system, in lab tests.

The discovery, published in the journal Cell Stem Cell, adds weight to claims that Zika is causing brain abnormalities in babies.

However, the US researchers caution this is not yet the conclusive link.

There have been more than 4,800 confirmed and suspected cases of babies born with small brains - microcephaly - in Brazil.

It is widely thought that the Zika outbreak is to blame, but this has not been scientifically confirmed.

The team from the Johns Hopkins, Florida State and Emory universities infected a range of tissue samples with Zika virus for two hours and then analysed the samples three days later.

The virus was able to infect up to 90% of neural progenitor cells in a sample leading to nearly a third of cells dying and the growth of the rest being disrupted.

A similar effect in a developing brain could have devastating results.

Zika virus imagesImage copyrightFiocruz
Image captionOne of the first images of the Zika virus taken from a patient in the outbreak in South America

The virus was able to infect only 10% of other tissue types tested including more advanced brain cells, kidney cells and embryonic stem cells.

Prof Guo-li Ming, one of the researchers, said the findings were significant and represented a first step to understanding the link between microcephaly and Zika.

She told the BBC News website: "Neural progenitor cells are especially vulnerable to the Zika virus.

"They are giving rise to the cortex - the primary part [of the brain] that shows reduced volume in microcephaly.

"But this research does not provide the direct evidence that Zika virus is the cause for microcephaly."

She said studies looking at brain organoids or animal studies were still needed.

Analysis

David Shukman, Science editor, BBC News

In the overcrowded hospitals of Recife, the teeming Brazilian city at the epicentre of the crisis, medics have long assumed that the Zika virus is to blame.

In a sweltering waiting room last month, where anxious mothers were clutching babies with abnormally small heads, Dr Angela Rocha told me that she was convinced of the link.

In a normal year, she said, she might see five suspected cases of microcephaly while in the previous few months she had seen more than 200.

When I asked whether it would be wise to wait for a full scientific analysis with peer-reviewed conclusions, she looked at me with scorn.

With so many cases, and more in prospect after the next rainy season, we do not have time to wait, she said.

It is unclear why these cells should be so vulnerable, but it appears they do not mount an immune response to Zika infection.

While not definitive, the study adds to mounting evidence including Zika being discovered in the brains of dead babies as well as in amniotic fluid.

Brain development researcher Dr Madeline Lancaster, from the MRC Laboratory of Molecular Biology, said the study was a "significant step forward".

She told the BBC News website: "The effect they see could well explain the surge in microcephaly and it opens the door for many further studies into how the virus is affecting stem cells and whether this affects their ability to generate neurons in the developing brain.

"I think it's a very important contribution and is extremely timely."

But she agreed with the researchers that more research was needed to "test whether Zika does indeed affect neuron generation and brain size" as well as how it crosses the placenta.

Dr Bruce Aylward, from the World Health Organization, said the evidence was mounting that Zika was causing microcephaly and another condition - Guillain-Barre syndrome.

He said: "Since the public health emergency of international concern was declared back in February, the evidence that there may be a causal relationship has continued to accumulate

http://www.bbc.com/news/health-35725744

 

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How the Zika virus is probably causing birth defects in children

 

It may be changing how brain cells express genes

GettyImages-508237732.0.jpg
 
(Mario Tama/Getty Images)

Strong evidence suggests the mosquito-borne Zika virus is causing infants to be born with birth defects — and a lab model provides clues on how it happens. The virus is capable of infecting the cells that form the brain's outer layer, making them more susceptible to death and preventing them from forming new tissue. Though this study took place in a lab dish, rather than in a human person, it may explain how Zika stunts brain development.

 

THE VIRUS IS CAPABLE OF INFECTING THE CELLS THAT FORM THE BRAIN'S OUTER LAYER

 

The findings come from a new study published in Cell Stem Cell that looked at how the Zika virus interacted with human stem cells grown in a lab. The stem cells were made to mimic the types of cells that eventually form the cortex — the brain's outer layer. Within three days of being exposed to Zika, up to 90 percent of these cells had been infected. Not only did this lead to massive cell death, but the infected cells were reprogrammed to produce even more copies of the Zika virus. These experiments could eventually help doctors find new drugs to stop the virus' damage on unborn babies, the study authors argue.

The study is the first to show how Zika may be causing children to be born with abnormally small heads — a condition known as microcephaly. Researchers strongly suspect that the two conditions may be linked, due to the recent spread of both in Central and South America. Since March of last year, up to 1.5 million people in Brazil alone have been infected with the virus, according to the World Health Organization. The outbreak has coincided with a massive spike in cases of microcephaly in Brazil. Zika has also been found in the brains of developing fetuses, indicating that the virus can be transmitted from mother to child.

Today's research still does not confirm that Zika is causing these birth defects. The researchers only looked at how the virus interacts with individual brain cells in a lab setting, indicating which cells may be susceptible to the virus. To truly confirm Zika is behind microcephaly, the researchers would need to observe how Zika damages the entire brain. "Maybe the next step will be to use Zika on a 3D mini-brain to look at a more direct link," said one of the study authors Zhexing Wen, a neurobiologist at Johns Hopkins University School of Medicine.

 

 

This image shows cell death of the stem cells in red; the ZIKA virus is highlighted green. (Sarah C. Ogden)

But the study did reveal the extent to which Zika may be damaging the developing brain's cells. When Zika was introduced into a plate of stem cells, the virus altered how the cells' genes were expressed, reprogramming the cells to become mini Zika-producing factories. The virus also seemed to turn off the genes needed to fight off viral infection, causing many of the stem cells to die. And the genes that govern cell division were disrupted as well, indicating that the cells couldn’t divide to form new brain tissue.

http://www.theverge.com/2016/3/4/11161360/zika-virus-birth-defect-causes-fetus-brain-study

 

 

THERE ARE STILL MANY UNKNOWNS ABOUT ZIKA'S ROLE ON THE DEVELOPING FETUS

Even if these experiments don’t confirm a direct Zika-microcephaly link, they could be used to screen for drugs that stop Zika from harming the brain, according to Wen. Researchers could add different compounds to the stem cells when they are exposed to Zika, to see which drugs work best at preventing infection or cell death.

Yet there are still many unknowns about Zika's role on the developing fetus that need to be answered, according to Sika Zheng, an assistant professor of biomedical sciences at University of California, Riverside, who was not involved in the study. It’s still unclear if Zika is harming the brain itself, or if it’s causing fevers and other symptoms in the mother that are indirectly damaging the baby's brain. And if Zika is directly harming the brain, how is it crossing the blood-brain barrier? "The single most important evidence is looking to see if this virus can get into the brain [in a living patient]," said Zheng.

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Toward an Understanding of Zika's Neurological Dangers

New research comes closer to connecting the virus with microcephaly and Guillain-Barré.

The ubiquitous caveat in stories about the Zika virus thus far: Despite the huge uptick of cases in the birth defect microcephaly in Brazil, and despite the verrrrry suspicious correlation of this uptick with the arrival of Zika in the country, we don’t know for certain that Zika causes microcephaly. The same goes for the neurological disorder Guillain-Barré, cases of which have also climbed in time with the Zika outbreak.

“More research is needed,” scientists and government officials have chorused, declaring a quest to get good science on the virus as quickly as possible. And it’s starting to show results.

A new study published Friday in Cell Stem Cell shows how Zika affects neural stem cells, which appear to be particularly vulnerable to the virus. This may be the mechanism by which Zika could cause microcephaly, a condition in which a baby is born with an unusually small head due to incomplete brain development.

Researchers examined the effects of a strain of Zika virus (not the same strain currently circulating in the Americas, but the original strain, from Africa) on three different kinds of cells: induced pluripotent stem cells (stem cells with the potential to turn into any kind of cell in the body); human cortical neural progenitor cells, or NPCs (stem cells that are destined to become brain cells, specifically); and immature cortical neurons (young brain cells).

They found that the Zika virus absolutely loves cortical neural progenitor cells. It just loves ‘em. Even with a relatively small viral load (one virus for every 10 cells), after three days, 65 to 90 percent of the brain stem cells were infected, meaning the cells were reproducing the virus.

“These NPCs after infection, they become a viral factory,” says Guo-Li Ming, a professor of neurology at Johns Hopkins University and one of the study’s authors. In contrast, the infection rate in the pluripotent stem cells and the immature neural cells was pretty low—under 20 percent for each.

As they’re making all these viruses, the NPCs’ growth and reproduction cycle is slowing down, and the cells are dying. Because a fetus’s nervous system is mostly developed by the second trimester, this research suggests that fetuses would be most at risk during the first trimester, when NPCs abound. Research has already shown that Zika can cross the placenta—the virus was found in the amniotic fluid of two Brazilian pregnant women whose fetuses were diagnosed with microcephaly. Once it does cross that barrier, it may target these brain stem cells, which could be what’s causing the condition.

This week also saw research advancing the connection between Zika and Guillain-Barré: A study published in The Lancet on Monday offered the first real evidence that Zika can cause Guillain-Barré syndrome—an autoimmune disease in which the immune system targets a person’s nervous system. Guillain-Barré can completely paralyze people, to the point where they can’t breathe. Most people recover, though they may not fully regain their strength, according to the National Institutes of Health.

The Lancet study looked at 42 patients who were diagnosed with Guillain-Barré at a Tahiti hospital during the 2013-2014 Zika outbreak in French Polynesia. Ninety-three percent of the Guillain-Barré patients had anti-Zika antibodies in their blood, and 88 percent of them reported that they’d had other Zika-esque symptoms within six days of the onset of their neurological symptoms.

http://www.theatlantic.com/health/archive/2016/03/study-how-zika-could-cause-microcephaly/472149/

 

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Zika virus kills developing brain cells

By Gretchen Vogel

As fear of the Zika virus spreads nearly as quickly as the pathogen itself, two new laboratory studies offer the first solid evidence for how it could cause brain defects in babies: The virus appears to preferentially kill developing brain cells. The observation bolsters the growing case for a connection between the virus, which is spreading rapidly across Latin America, and an increase in the number of cases of microcephaly, a birth defect in which the brain fails to grow properly. The new work, done independently by two groups, shows that the virus readily infects neural stem cells—the precursors of neurons and other brain cells—whether they are grown on cell culture plates or coaxed to form 3D minibrains called cerebral organoids.

The work “is going to be very important,” says Madeline Lancaster, a developmental biologist who studies human brain development at the Medical Research Council Laboratory of Molecular Biology in Cambridge, U.K. The results “are quite consistent with what you’re seeing in the babies with microcephaly.”

Zika virus, named after a forest in Uganda where it was first isolated decades ago, usually causes only mild symptoms in people, including fever and rash. But after the virus started spreading across northeastern Brazil last year, doctors there noticed a striking increase in the number of babies born with microcephaly. Many of the mothers reported having symptoms consistent with Zika infection during their pregnancies. But it has been difficult to prove a link between the virus and the birth defects because blood tests for Zika virus are only accurate for about a week after infection.

Nevertheless, circumstantial evidence has accumulated. Researchers have identified the virus in amniotic fluid of pregnant women whose fetuses were diagnosed with microcephaly and also in the brain tissue of a fetus diagnosed with the disorder. But because researchers had conducted scant research on the virus before this year, they had little data to suggest how the virus could cause such damage.

To gauge the virus’s possible effects on the developing brain, researchers at Johns Hopkins University in Baltimore, Maryland, and Florida State University in Tallahassee used induced pluripotent stem (iPS) cells to grow, in lab dishes, immature brain cells called human cortical neural progenitor cells. (iPS cells are adult cells that have been reprogrammed into stem cells that can grow into most of the tissues in the body.) They then exposed the neural progenitor cells to a lab strain of Zika virus.

The virus readily infected the neural stem cells, neuroscientists Hongjun Song and Guo-li Ming, virologist Hengli Tang, and their colleagues report today in Cell Stem Cell. Three days after the virus was applied, 85% of the cells in the culture dishes were infected. In contrast, when the virus was applied to cultures of fetal kidney cells, embryonic stem cells, and undifferentiated iPS cells, it infected fewer than 10% of the cells by day 3. Immature neurons derived from the neural progenitor cells were also less susceptible to the virus; 3 days after receiving a dose of the virus, fewer than 20% of those cells were infected.

The researchers noticed that the infected progenitor cells were not killed right away. Instead, the virus “hijacked the cells,” using the cellular machinery to replicate themselves, Song says. That helped the virus to spread quickly through the cell population, he says.  His team also reports that infected cells grew more slowly and had interrupted cell division cycles, which could also contribute to microcephaly.

In a separate set of experiments, other researchers found that the virus can hamper the growth of another type of neural stem cell. In a preprint posted online on 2 March, neuroscientist Patricia Garcez and stem cell researcher Stevens Rehen at the D'Or Institute for Research and Education in Rio de Janiero, Brazil, report growing human iPS cells into clusters of neural stem cells called neurospheres, as well as into 3D organoids that in some ways resemble a miniature version of the human brain. When they infected the growing cells with Zika virus isolated from a Brazilian patient, the virus quickly killed most of the neurospheres and left the few survivors small and misshapen. Infected organoids grew to less than half their normal size.

Lancaster says the results echo earlier studies of gene mutations that cause microcephaly, which also affect neural progenitor cells. “You have two very different causes of microcephaly, but you see something very similar happening: a depletion of neural stem cells, and that would lead to fewer neurons” in the developing brain, she says.

Plenty of questions about the Zika virus and its apparent link to birth defects remain unanswered. Both Garcez and Song say they are now repeating their experiments with other viruses, including dengue, a virus closely related to Zika that is prevalent in the regions currently affected by the outbreak. (Some scientists suspect that previous exposure to other viruses could affect the outcome of Zika infections.) Researchers also still need to figure out how the virus crosses the placenta and infects the fetus directly, something most viruses can’t do.

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A Zika breakthrough: Scientists detail how virus can attack fetal brain

 
    

U.S. researchers make breakthrough discovery on how Zika virus can cause rare birth defect

 
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U.S. researchers say they have discovered how the Zika virus can cause microcephaly, a rare birth defect in which babies are born with abnormally small heads and brain problems. (Florida State University)

A team of U.S. researchers announced Friday that they believe they have discovered a mechanism for how the Zika virus can cause the rare birth defect known as microcephaly, in which babies are born with abnormally small heads and underdeveloped brains.

Working with lab-grown human stem cells, scientists found that the virus selectively infected cells forming the brain's cortex, the thin outer layer of folded gray matter. Its assault made those cells more likely to die and less likely to divide normally and make new brain cells.

The finding by researchers from Johns Hopkins University, Florida State University and Emory University offers among the strongest evidence yet of how Zika is harming fetuses. Health authorities are increasingly convinced that the mosquito-borne virus has caused microcephaly in hundreds of babies in Brazil, the epicenter of the Zika outbreak that is sweeping through the Americas.

 
 

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"It strengthens the case that Zika is a culprit behind microcephaly," said Joseph Gleeson, an investigator for the Howard Hughes Medical Institute, who was not involved in the study. "It's a very important piece in the puzzle."

[In the U.S., 9 Zika pregnancies include 2 miscarriages and 1 baby with 'severe microcephaly']

Researchers have already documented an increase of microcephaly cases coinciding with the outbreak and have found evidence of the virus in brains of newborns who died, as well as in fluid from the placenta of infected pregnant women.

But one of the missing pieces has been information about how Zika can slow or halt brain development in an unborn child. While Friday's study doesn'tdefinitively prove that the disease causes microcephaly, it strengthens the link between the two by showing cells from the brain's cortex are vulnerable to attack from the virus, according Guo-li Ming, a Johns Hopkins neurologist and one of the lead authors.

"What we show is the first piece of evidence" consistent with the hypothesis that Zika infections cause microcephaly, said Hengli Tang, a virologist at Florida State University and another lead author. "We're literally the first people in the world to know this, to know that this virus can infect these very important cells and interfere with their function."

The study, published in the academic journal Cell Stem Cell, answers a key question about the viral path of attack, said Kristen Brennand, a stem cell biologist at the Icahn School of Medicine at Mount Sinai Medical Center in New York.

The Zika virus, explained

 
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Everything you ever wanted to know about the Zika virus and its spread across North and South America. (Daron Taylor,Claritza Jimenez/The Washington Post)

The researchers took human stem cells, exposed them to a strain of Zika and found that within three days, the virus had attacked specific kinds of cells critical to development of the brain's cortex. These cells became infected and also were hijacked to make new copies of the virus. Many died; others were damaged and unable to replicate.

[Zika is expected to infect 1 in 5 Puerto Ricans, increasing threat to rest of U.S.]

Researchers used the original Zika strain, first discovered in Uganda in 1947. That strain is 89 percent identical to the current strain that has spread rapidly to about three dozen countries and territories, primarily in the Americas.

The authors and other experts noted that the study, which involved dozens of scientists working at four labs at three universities, still only goes so far and must be followed with additional research. It took place in a controlled environment, with lab-grown stem cells.

Have you had an experience with Zika? We'd like to hear from you.

But Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine, said its findings offer "potentially important" new information about the link between Zika and microcephaly.

"This paper points to a mechanism that's plausible and makes sense," Hotez said. "It gives us a clue as to why the virus inhibits the brain growth of a fetus. ... It adds an important brick in the wall that says Zika is the cause of this epidemic of microcephaly we're seeing. These kinds of studies can help melt away all the other theories."

https://www.washingtonpost.com/news/to-your-health/wp/2016/03/04/a-zika-breakthrough-scientists-detail-how-virus-attacks-fetal-brain/

 

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Study shows how Zika virus could cause fetal brain defects

NEW YORK | BY ANDREW M. SEAMAN
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Lediane da Silva, who is eight months pregnant, is seen in the shanty town of Beco do Sururu, Recife, Brazil, January 29, 2016.
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The Zika virus is capable of quickly infecting and harming developing fetal brain cells, scientists said on Friday in a study that provides insight into how the virus might cause the birth defect microcephaly in fetuses exposed in the womb.

The researchers said their study, published in the journal Cell Stem Cell, does not provide proof of a direct causal link between Zika and microcephaly, but it does identify where the virus may be inflicting the most damage in developing fetuses.

The mosquito-borne virus infects a kind of neural stem cell that goes on to form the cerebral cortex, the brain's outer layer responsible for intellectual capabilities and higher mental functions, the study showed.

Researchers found that these cells, exposed to the virus in laboratory dishes, were infected within three days, turned into "virus factories" for viral replication and died more quickly than normal.

"Our study shows once the virus gets to the brain it can reach these very important cells," researcher Hengli Tang, the study's lead author from Florida State University, said in an interview.

Tang said the study suggests the virus would be capable of doing the damage seen in microcephaly, a condition defined by unusually small heads that can result in developmental problems.

Zika has been linked to numerous cases of microcephaly in Brazil and is spreading rapidly in Latin America and Caribbean nations, prompting the World Health Organization to declare a global public health emergency.

Much remains unknown about Zika, including whether the virus actually causes microcephaly. Brazil said it has confirmed more than 640 cases of microcephaly, and considers most of them to be related to Zika infections in the mothers. Brazil is investigating more than 4,200 additional suspected cases of microcephaly.

"By determining whether Zika virus infects cells in the brain and what happens to a cell that is infected, this paper begins to tackle questions surrounding how a virus that had previously been known to cause a mild illness could be linked to microcephaly," Amelia Pinto, a Saint Louis University expert on viruses transmitted by arthropods such as mosquitoes and ticks, said in a statement.

Tang said future studies will be needed to prove whether or not Zika causes microcephaly.

"We know people would be interested in knowing this information, but a lot still needs to be done," Tang said. "Ultimately the proof would need to come from the clinical side and animal studies."

The researchers are currently growing in the laboratory what they called "mini-brains" composed of the stem cells to see how the virus may affect development over a longer period of time.

Traces of Zika virus have been found in the bodily fluids and tissue of mothers and babies affected by microcephaly.

Dr. Lyle Petersen, director of the division of vector-borne diseases at the U.S. Centers for Disease Control and Prevention, told a news briefing on Wednesday at the Pan American Health Organization in Washington that there are numerous lines of evidence now linking Zika with microcephaly.

"I don't think there is any question about that any longer," Petersen said.

 

 

(Reporting by Andrew M. Seaman in New York; Additional reporting by Julie Steenhuysen in Chicago; Editing by Will Dunham)

http://www.reuters.com/article/us-health-zika-brain-idUSKCN0W6249

 

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Zika Infects Neural Progenitors

Scientists provide a potential biological link between Zika virus infection and microcephaly.

By  | March 4, 2016

ZikaNeurons.jpgZika virus (green) infects human neural progenitors and leads to cell death (red).SARAH C. OGDENLaboratory-grown human neural progenitor cells, which can give rise to the kind of neurons and glia found in the brain, can be infected and killed by a strain of Zika virus, according to a report published today (March 4) in Cell Stem Cell. The study, albeit preliminary, offers the first suggestion of how Zika infection of pregnant women might lead to microcephaly in their babies.

“The study demonstrates that human neuron-like cells can be infected with Zika virus and that infection leads to death and reduced growth of the infected cells,” said microbiologist and immunologistAndrew Pekosz of Johns Hopkins University who was not involved in the study. “This is important because this may be a way to study the damage induced directly by infection.”

The number of infants born with microcephaly—a neurological condition in which the brain and skull fail to grow at a normal pace—have risen dramatically in Brazil since late 2015. An outbreak of Zika virus infections in the country last year is strongly suspected to be the cause, but while the virus has been detected in the amniotic fluid of two babies and the brain tissue of one fetus with microcephaly, so far no causal link between the condition and the mosquito-borne pathogen has been made.

Neurologist and neuroscientist Guo-li Ming of Johns Hopkins School of Medicine is an expert in human brain development and mental disorders. Because analyzing actual human brain development is practically impossible, she uses human neural progenitor cells derived from induced pluripotent stem cells (iPSCs) as a model system.

On hearing about the Zika-microcephaly crisis in Brazil, Ming realized she had a unique opportunity to examine whether human neural progenitor cells might be susceptible to infection. Partnering with scientists at Florida State University who study Zika virus, Ming’s team inoculated the neural progenitors as well as human iPSCs, embryonic stem cells and immature neurons and compared the extent of the resulting infections. While less than 20 percent of the iPSCs, embryonic stem cells and neurons became infected, the infection of the neural progenitors was “really striking,” said Ming. Up to 90 percent of the cells contained the virus and “what is a bit scary to us,” she said, “is that we found these progenitor cells can actually spit out more virus”—with the potential to infect yet more progenitor cells.

Ming and colleagues showed that infection of the progenitors either killed the cells or slowed their proliferation significantly.

Neural progenitors “give rise to the larger population of neurons and glial cells of the brain,” Ming said. “So if they are infected and they die or have retarded growth we think that could have an impact on the neurons they will produce.” As yet, however, the team has no evidence for how such infection might affect brain development.

“These laboratory findings may begin to unearth some possible mechanisms by which Zika virus infects and damages brain tissue,” said virologist Ian Mackay of the University of Queensland in Brisbane, Australia, who did not participate in the research. “But they are one step on a long path to understanding the mechanism in humans and should be considered with care and in context.”

For one thing, he said, the virus strain used in the study differs to the one responsible for the ongoing outbreak in Latin America. “It is unclear whether this lab virus still behaves in the same way as do Zika viruses currently circulating in Brazilian mosquitoes and infected humans,” he said. Mackay added that the iPSC-derived neural cells grown in culture “may not yield infection results that accurately reflect disease processes in humans.”

To gain a better understanding of potential disease mechanism, Ming’s team plans to examine whether the infected neural progenitor cells lead to abnormal development of brain organoids—cultured mini brainsderived from human iPSCs. “But still this won’t tell you directly if that’s what’s happening during pregnancies,” she said, “Ultimately, that evidence has to come from the clinic.”

Indeed, agreed Mackay, “much work remains to be done to understand whether Zika virus is capable of causing the diseases or diagnoses with which it is being presumptively associated.”

H. Tang et al., “Zika virus infects human cortical neural precursors and attenuates their growth,” Cell Stem Cell, doi:10.1016/j.stem.2016.02.016, 2016.

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Zika virus, virology, neuroscience, microcephaly, disease/medicine and cell & molecular biology
http://www.the-scientist.com/?articles.view/articleNo/45506/title/Zika-Infects-Neural-Progenitors/
 
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Evidence Zika Virus Can Cause Serious Complications Growing

Evidence virus can cause infant brain damage, a paralyzing neurological disorder

 
A woman who is six months pregnant shows a photo of her ultrasound at the IMIP hospital in Brazil. The woman was struck with the Zika virus and was worried about the health of her baby, but her baby's ultrasound scan and other exams indicated everything was normal.ENLARGE
A woman who is six months pregnant shows a photo of her ultrasound at the IMIP hospital in Brazil. The woman was struck with the Zika virus and was worried about the health of her baby, but her baby's ultrasound scan and other exams indicated everything was normal. PHOTO: ASSOCIATED PRESS
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Evidence that Zika virus can cause complications such as infant brain damage and a paralyzing neurological disorder is growing stronger, with new research made public this week.

In a series of lab experiments using stem cells, scientists showed the Zika virus infected cells that are critical for brain development, causing them to die or to stop functioning normally.  The researchers said the findings shed new light on how Zika might disrupt brain development in the unborn child of an infected pregnant woman, possibly leading to a birth defect known as microcephaly in which children are born with undersized skulls and brains.  The study was published Friday in the journal Cell Stem Cell.

Separate research published in the journal The Lancet this weekconfirmed a link between Zika and Guillain-Barre Syndrome, a neurological disorder in which the immune system attacks the nervous system, causing temporary but sometimes severe paralysis. Brazil, Colombia and El Salvador have all reported an increase in the number of cases of the disorder as Zika has swept through their populations.

The case-control study identified 42 patients who developed Guillain-Barre during an outbreak of Zika in French Polynesia in late 2013 and early 2014. All had Zika antibodies in their blood, compared with 56% of the members of a control group. Most weren’t severely affected; more than half could walk on their own three months after discharge from the hospital. But 12, or 29% of the group, required ventilators when paralysis affected their ability to breathe.

Health officials say they are operating on the assumption that Zika is linked to these complications, while continuing research to determine the nature of the links and whether there are other factors involved. “There are numerous lines of evidence now that link microcephaly with Zika virus, so I don’t think there’s any question about that any longer,” Lyle Petersen, director of the division of vector-borne diseases at the Centers for Disease Control and Prevention said in a briefing this week.

In the latest study, researchers at Johns Hopkins University School of Medicine, Florida State University and Emory University exposed a strain of Zika to several types of cells, including “parental” cells that give rise to the neurons that form the brain. The virus infected and “hijacked” the parental cells, spawning more copies of the virus, said Guo-li Ming, an author and professor of neurology at Johns Hopkins. Many of the infected cells died. Others showed gene disruptions that made it impossible to generate new cells effectively, she said.

“This is the first step toward understanding how Zika can affect brain development,” she said.

The next step is to figure out how the virus damages the cells, said Hongjun Song, also an author and neurology professor at Johns Hopkins.

Experts praised the research but said further work would need to be done to show how the lab findings apply to humans. “It’s a nice manuscript that I think is going to provide some information to help us understand how Zika virus might function and how it might impact fetal cells and the fetal brain,” said Catherine Y. Spong, acting director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

But, she said, “we need to know how this actually happens, and whether or not this is the mechanism that microcephaly is caused through.”

Other questions that need to be answered include how the virus passes from the mother to the fetus, and what impact it can have at different stages of pregnancy, she said.

The infection that the authors described doesn’t necessarily lead to microcephaly, said Amelia Pinto, an assistant professor of molecular microbiology and immunology at Saint Louis University, who studies immune responses to arboviruses such as West Nile virus and Zika. “West Nile can infect these cells and West Nile has never been known to cause microcephaly,” she said.

Write to Betsy McKay at [email protected]

http://www.wsj.com/articles/evidence-zika-virus-can-cause-serious-complications-growing-1457110802

 

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Zika Kills Cells Key to Fetal Brain Development, Study Says

By CATHERINE SAINT LOUIS

 

 

 

 

 

 

 

 

 

 

 

 

The Zika virus destroys cells that give rise to the brain cortex in the developing fetus, scientists reported on Friday.

 

 

 

 

The finding, published in the journal Cell Stem Cell, may help explain how the virus might cause microcephaly, or unusually small heads, in infants whose mothers are infected during pregnancy.

“It’s an important advance and a step forward to clearly demonstrate that the virus kills brain cells,” said Dr. Mark R. Schleiss, the director of pediatric infectious diseases and immunology at the University of Minnesota Medical School, who was not involved in the study.

But other experts cautioned that it was conducted with cells cultured in a laboratory and may not reflect the virus’s effects in humans.

“It might be that the results wouldn’t be the same in a living system of actual cortical stem cells,” said Dr. Catherine Y. Spong, the acting director of the National Institute of Child Health and Human Development.

“The act of culturing these cells to evaluate them in an in vitro system may make them more susceptible to infection,” she said.

In their experiments, researchers at Johns Hopkins and elsewhere cultured cells that eventually form the cortex, the outer layer responsible for many higher functions, of the fetal brain.

 

In the laboratory, the scientists exposed the so-called cortical neural progenitor cells to the Zika virus, along with two other types of cells present in early fetal development. Three days after exposure, 90 percent of the progenitor cells were infected, while the two other types were much less compromised.

“We found the cell types responsible for forming the cortex are the target of the Zika virus,” said Hongjun Song, a senior author of the new paper and a professor of neurology and neuroscience at Johns Hopkins University School of Medicine.

Infected cortical neural progenitor cells were unable to divide normally and died more often, the researchers found. The number of viable cells decreased 72 hours after infection, compared with those not infected with the Zika virus.

Dr. William B. Dobyns, a pediatric neurologist at Seattle Children’s Research Institute, called the new paper “highly significant.”

If the cells that should form the brain’s cortex in a fetus “aren’t growing fast enough,” he said, “you get a small brain, but on top of that there’s cell death, which means whatever the size the brain is, it will shrink.” That reduction may lead to a conspicuous space between the skull and brain.

Dr. Dobyns recently reviewed the brain scans of infants with microcephaly in Brazil.

“This paper fits like a glove what I’m seeing on the brain scans,” Dr. Dobyns said, including abnormalities like an unusual space between severely shrunken brains and the inner skull, and a relatively smooth brain surface.

But the new study does not prove that the Zika virus is responsible for a reported increase in microcephaly in Brazil. Experts await more convincing evidence from a study of roughly 5,000 pregnant women, mostly in Colombia, who all were infected with the Zika virus early in their pregnancies.

The World Health Organization does not expect the results from that study until June at the earliest.

Sara Cherry, an associate professor of microbiology at the University of Pennsylvania, called the new study “really important” but noted that Dr. Song and his colleagues “used a virus strain that’s quite distinct from what is circulating in Latin America.”

The research team, which includes scientists from Florida State University and Emory, nonetheless believes its experimental model can help explain how Zika affects nervous system development and can help provide a way to screen drugs that may “stop the entry of the virus into these brain cells,” said Dr. Guo-li Ming, a senior author of the study and a neurology professor at Johns Hopkins.

http://www.nytimes.com/2016/03/05/health/zika-virus-microcephaly-fetus-birth-defects.html?_r=0

 

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Studies strengthen link between Zika virus, birth defects

By Ralph Ellis, CNN

 

Updated 0436 GMT (1236 HKT) March 5, 2016 | Video Source: CNN

video_pinned_white_bg.jpg
 
 
 
 
 
 

Story highlights

  • One study says the virus appears to selectively infect cells in the brain's outer layer
  • Second study says ultrasounds found fetal abnormalities in 29% of women infected with Zika virus
 

(CNN)Scientists have long thought the Zika virus caused birth defects such as microcephaly, a condition in which a baby is born with a small head.

That belief was bolstered Friday by two studies published in medical journals.

Researchers working with lab-grown human stem cells "suspect they have discovered how the Zika virus probably causes microcephaly in fetuses," reported the journal Cell Stem Cell.

The researchers, working in the laboratory, determined the Zika virus selectively infects cells in the brain's cortex, or outer layer, making those cells "more likely to die and less likely to divide normally and make new brain cells," according to a press release from the journal.

While bolstering the connection between Zika virus and brain defects in babies, one of the researchers cautioned that it doesn't establish a conclusive link.

    Disease detectives hunt for Zika-microcephaly connection in Brazil

    "While the study doesn't definitely prove that Zika virus causes microcephaly, it's very telling that the cells that form the cortex are potentially susceptible to the virus and their growth could be disrupted by the virus," said Dr. Guo-li Ming, a professor at Johns Hopkins' Institute for Cell Engineering.

    These lab-grown cells might be used to screen for drugs that protect the cells, Cell Stem Cell said.

    Meanwhile, the New England Journal of Medicine reported on research conducted on 88 pregnant women in Rio de Janerio, one of the nations suffering most from the Zika virus.

    The scientists concluded that Zika infection during pregnancy has "grave outcomes, including fetal death, placental insufficiency, fetal growth, restriction, and [central nervous system] involvement," the journal said.

    5 things to know about the Zika virus

    The study said blood and urine tests found 72 of the 88 women had the Zika virus.

    Of the 42 infected women who had ultrasounds, major fetal abnormalities were found in 12 of them -- nearly a third.

    The abnormalities included microcephaly, calcification of the brain, abnormal flow of amniotic fluid, abnormal flow of blood to the brain and fetal deaths, the study said.

    "In summary, we believe that our findings provide further support for a link between maternal Zika infection and fetal and placental abnormalities that is not unlike that of other viruses that are known to cause congenital infections," the study said.

    Also on Friday, the World Health Organization released a situation report on Zika.

    The main points of the report:

    --Since January 2015, 41 countries and territories have reported Zika virus transmission.

    --Thirty-one of these countries and territories are in the Americas.

    --Increases in microcephaly and other neonatal malformations have been reported in Brazil and French Polynesia.

    --Increases in Guillain-Barré syndrome linked to Zika have been reported in eight countries and territories.

    The Zika virus is a flavivirus, part of the same family as yellow fever, West Nile, chikungunya and dengue. But unlike some of those viruses, there is no vaccine to prevent Zika or medicine to treat the infection.

    CNN's Debra Goldschmidt contributed to this report.

    http://edition.cnn.com/2016/03/04/health/zika-virus-and-birth-defects/index.html?eref=edition

     

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    Lab tests reveal link between Zika and microcephaly

    US scientists say they have discovered a evidence of a link between the Zika virus and brain deformation in fetuses. Tests revealed that the virus appeared to target cells crucial to brain development.

    Brasilien Zika Virus - Mikrozephalie - Mutter mit Baby

    Scientists claimed that laboratory tests had yielded the first evidence of a biological link between the virus and Zika.

    Studies showed the virus targeted cells that were important for the development of the brain, before disabling or destroying them. The findings provide a significant breakthrough in linking the mosquito-born pathogen with microcephaly, according to Guo-li Ming, a professor of neurology at Johns Hopkins' Institute for Cell Engineering, one of the report's co-authors.

    The research team used lab-grown human stem cells to look at which type of cells were selectively infected by the Zika virus. Scientists looked at three brain cell types, and found that 90 percent of human neural progenitor cells (hNPCs) were infected within three days - with many of them already dead within that time.

    Like other viruses, Zika hijacks cellular machinery to make copies of itself and eventually destroys infected host cells.

    'Telling' pattern of infection

    The hNPCs are crucial for the development of the cortex - or outer layer - of fetal brains, and the findings would be consistent with the theory that Zika can cause microcephaly.

     
     
    Watch video12:07

    Brazil in battle against Zika virus

    "It is very telling that the cells that form the cortex are potentially susceptible to the virus," said Ming.

    Co-author Hongjun Song said that the results - published in the journal Stem Cell - would help identify new treatments. "Now that we know cortical neural progenitor cells are the vulnerable cells, they can likely also be used to quickly screen potential new therapies," said Song.

    Outside of pregnancy, Zika is normally no more threatening than a bad cold or a mild case of the flu.

    Evidence piling up

    An apparent link with microcephaly emerged as the cases of infection with the virus spread, coinciding with an increase in brain defects. In Brazil, the country apparently worst-hit, the number of confirmed and suspected cases of microcephaly associated with Zika this week rose from to 4,863 from 4,690 a week earlier.

    The World Health Organization (WHO) said on Friday that there was mounting evidence of a link between the virus and microcephaly, as well as the rare paralysis-causing Guillain-Barre syndrome.

    The WHO Emergency Committee is due to meet on Tuesday to review "evolving information" and to re-examine recommendations on travel, trade and mosquito control.

    http://www.dw.com/en/lab-tests-reveal-link-between-zika-and-microcephaly/a-19096257

     

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    ATCC Supporting Zika Virus Research

    Discover more at www.atcc.org

    MANASSAS, Va., Feb. 5, 2016 /PRNewswire-USNewswire/ -- ATCC, the premier global biological materials resource and standards organization, is poised to assist the medical and life science researchers that are working to address the evolving concerns around Zika Virus infection.  

    Zika virus is a single-stranded RNA virus of the Flaviviridae family, genus Flavivirus, which also includes the West Nile, Dengue and Chikungunya Viruses. Zika virus is transmitted to humans primarily through the bite of an infected Aedes species mosquito. For more information on the disease, please refer to the CDC website.

    The virus was first deposited into ATCC by Dr. Jordi Casals of the Rockefeller Foundation Virus Laboratory in 1953. Since that time ATCC has made the Zika virus (ATCC® VR-84™) strain MR766 available for research purposes to qualified scientists and laboratories, on a global basis, through a highly vetted process that requires them to demonstrate they have appropriate facilities and safety programs in place (in accordance with Biosafety in Microbiological and Biomedical Laboratories (BMBL) guidelines). ATCC is now working to respond to the greatly increased demand for the Zika virus in an effort to support a better understanding of its biology and to foster development of accurate and dependable diagnostic tests.

    In addition to ATCC, three stains of the Zika virus are available through BEI Resources, a NIAID Biorepository established to support basic research and develop improved diagnostic tests, vaccines, and therapies.  Registration and approval is required by NIAID to obtain these viruses. www.beiresources.org

    As the biomedical and scientific communities continue to respond to the public health concerns represented by the Zika Virus, ATCC will work closely with them to ensure they have the research and biological reference materials they need for their work. For additional information, please refer to the Zika Virus FAQ on our website.

    About ATCC

    ATCC collaborates with and supports the scientific community with industry-standard products and innovative solutions. With the world's largest and most diverse collection of human and animal cell lines, molecular genomic tools, microorganisms, biological products, and standards ATCC is a trusted biological resource for the worldwide research community. Together, the people of ATCC share in its mission to acquire, authenticate, preserve, develop, and distribute biological materials and information for the advancement of scientific knowledge. Founded in 1925, ATCC is a non-profit organization with headquarters in Manassas, VA. Discover more at www.atcc.org.

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    FRIDAY, MARCH 4, 2016

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    03/04/2016 11:45 am

    Hengli Tang, professor of biological science at Florida State.

    Hengli Tang, professor of biological science at Florida State.

    Zika virus FAQ (PDF)

    Florida State University researchers have made a major breakthrough in the quest to learn whether the Zika virus is linked to birth defects with the discovery that the virus is directly targeting brain development cells and stunting their growth.

    This is the first major finding by scientists that shows that these critical cells are a target of the virus and also negatively affected by it. Hengli Tang, professor of biological science at FSU, is a lead author of the study published today (March 4) in the academic journal Cell Stem Cell.

    “We’re trying to fill the knowledge gap between infection and the neurological defects,” Tang said. “This research is the very first step in that, but it’s answering a critical question. It enables us to focus the research. Now you can be studying the virus in the right cell type, screening your drugs on the right cell type and studying the biology of the right cell type.”

    Though the Zika virus was discovered in 1947, there is very little known about how it works and its potential health implications, especially among pregnant women. Anecdotal evidence has suggested a link to microcephaly, a condition where a child is born with an abnormally small head as a result of incomplete brain development.

    Tang, along with researchers at Johns Hopkins University and Emory University, found that the virus directly targets a cell type called human embryonic cortical neural progenitors in as little as three days after being exposed to the virus. They also discovered that these infected cells replicate the Zika virus, posing potential treatment problems, and that the virus is directly interfering with cell growth and function. Some of the cells died after being infected.

    “Potentially, this could explain why there is a link to microcephaly, but there is a lot more work needed to show the direct causal effect,” said Guo-Li Ming, professor of neurology at Johns Hopkins University.

    The research took a remarkably quick path. Because of the public health implications, researchers worldwide have been working around the clock to study how the virus works and its potential targets.

    According to the World Health Organization, 48 countries have reported local transmission of the Zika virus.

    About a month ago, a research team led by Johns Hopkins University neurology Professors Hongjun Song and Ming brought neural stem cells to FSU where Tang and his graduate students infected them with the virus and began monitoring them. A few weeks later, they were transported to Emory so scientists there could analyze changes in gene expression caused by the virus.  

    Tang had been funded by the National Institutes of Health to study the Dengue virus, which is similar to the Zika virus, and was in the unique position of already running a lab equipped to handle and study samples of the virus. Song and Ming, who went to graduate school with Tang, were experts on the neural cells that they believed the virus was targeting.

    The three labs will continue to collaborate and also tackle various aspects of the disease separately. Tang is investigating how it enters the cell and then how it specifically disrupts the normal cell processes. Ming is using 3D models of brains to further examine the link between the neural progenitor cells and microcephaly. And Song is investigating why the virus is going after neural progenitor cells as opposed to other cell types.   

    Many questions still remain about the virus, but this discovery is the pivotal first step.

    “It’s significant because we’re literally the first people in the world to know this, to know that this virus can infect these very important cells and interfere with their function,” Tang said. “Research is rewarding in general, but when you have something this timely and this clinically relevant, it’s extra satisfying because we’ll be helping people in the long run.”

    Other authors on the paper are Florida State University researcher Ruth Didier and graduate students Christy Hammack, Sarah Ogden and Emily Lee;  Zhexing Wen, Xuyu Qian and Kimberly Christian from Johns Hopkins University; and Yujing Li, Bing Ya, Feiran Zhang and Peng Jin from Emory University.

    The research was funded by Florida State University, the Maryland Stem Cell Research Fund and the National Institutes of Health.

     
    • 3 weeks later...
    niman Grand Master

    niman

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    Zika and Birth Defects: The Evidence Mounts

    Posted on  by Dr. Francis Collins
    Zike virus infection

    Caption: Human neural progenitor cells (gray) infected with Zika virus (green) increased the enzyme caspase-3 (red), suggesting increased cell death.
    Credit: Sarah C. Ogden, Florida State University, Tallahassee

    Recently, public health officials have raised major concerns over the disturbing spread of the mosquito-borne Zika virus among people living in and traveling to many parts of Central and South America [1]. While the symptoms of Zika infection are typically mild, grave concerns have arisen about its potential impact during pregnancy. The concerns stem from the unusual number of births of children with microcephaly, a very serious condition characterized by a small head and damaged brain, coinciding with the spread of Zika virus. Now, two new studies strengthen the connection between Zika and an array of birth defects, including, but not limited to, microcephaly.

    In the first study, NIH-funded laboratory researchers show that Zika virus can infect and kill human neural progenitor cells [2]. Those progenitor cells give rise to the cerebral cortex, a portion of the brain often affected in children with microcephaly. The second study, involving a small cohort of women diagnosed with Zika virus during their pregnancies in Rio de Janeiro, Brazil, suggests that the attack rate is disturbingly high, and microcephaly is just one of many risks to the developing fetus. [3]

    The NIH-supported study, described in a recent issue of Cell Stem Cell, was led by Guo-li Ming and Hongjun Song of Johns Hopkins University School of Medicine, Baltimore, and Hengli Tang of Florida State University, Tallahassee. Their research teams turned to human induced pluripotent stem (iPS) cells, derived from skin biopsies, to produce human neural progenitor cells (hNPCs). These cells are readily found in the developing brain and are capable of becoming neurons in the cerebral cortex.

    The researchers found that Zika virus could readily infect those neural progenitors in lab dishes. In fact, within three days of inoculation, the virus had infected 65 to 90 percent of the cells. The infection also led to a 30 percent reduction in viable hNPCs, as some cells died and others grew more slowly. In another important experiment, the group discovered that, once infected, a neural progenitor cell turns into “a virus factory.” In other words, the virus exploits the cell’s own machinery to produce and release more Zika to infect more cells.

    While these findings will need to be confirmed in clinical studies, they suggest for the first time that Zika virus can directly target these essential neural cells. They also help to explain how Zika infection could cause harm to the developing brain, providing a possible link to microcephaly.

    Unfortunately, it now appears that microcephaly isn’t the only cause for worry about children exposed to Zika virus in the womb. In the second study, reported recently inThe New England Journal of Medicine, a team of U.S. and Brazilian researchers enrolled 88 healthy pregnant Brazilian women who within the past five days had developed a red skin rash, one of the symptoms associated with Zika infection. Seventy-two of these women were later confirmed by blood and/or urine tests to have Zika virus, and 42 of those agreed to undergo an abdominal ultrasound.

    Of the Zika-infected women, almost a third had developing babies that showed signs of very serious abnormalities by ultrasound. Five babies showed growth restrictions with or without microcephaly. Seven had other abnormalities of the central nervous system. Seven babies showed abnormally low levels of amniotic fluid or blood flow to the brain or umbilical cord. Doctors delivered one of the babies by emergency C-section due to a dangerous lack of amniotic fluid. Two babies in the study were stillborn just weeks before their due dates. None of the 16 Zika-uninfected women had pregnancies with fetal abnormalities.

    These preliminary findings suggest that exposure to Zika virus is risky at any stage of pregnancy—even for developing babies that don’t appear to have microcephaly or other malformations. Further research is urgently needed, and these researchers have now enrolled a total of 280 Brazilian women into their ongoing study. They’ll also continue to follow the outcomes for these women and their children over the coming months.

    Taken together, these studies strengthen the case that the Zika virus may well be behind the deeply troubling rise in microcephaly in Brazil. These new developments raise the question of why the ability of Zika virus to cause birth defects wasn’t previously known—after all, this virus has been around for a long time (it was originally described in 1947 in the Zika forest in Uganda). One possibility is that in endemic areas nearly all individuals are infected as children, have a mild illness, and then develop lifelong immunity. Only in the situation where a previously unexposed population encounters the virus in adulthood is the risk of active infection in pregnancy, and subsequent birth defects in the offspring, possible. (Scholars of virology will recognize this phenomenon as having similarities to rubella, or “German measles.”) The NIH is now working aggressively to develop a vaccine. But there are still many steps in development and testing before a vaccine could be made available to vulnerable populations. Meanwhile, CDC recommendations for travelers should be scrutinized by everyone.

    References:

    [1] Zika virus disease in the United States, 2015-2016. Centers for Disease Control and Prevention. 2016 Mar 9.

    [2] Zika virus infects human cortical neural progenitors and attenuates their growth. Tang H, Hammack C, Ogden SC, Wen Z, Qian X, Li Y, Yao B, Shin J, Zhang F, Lee EM, Christian KM, Didier RA, Jin P, Song H, Ming G. Cell Stem Cell. 2016 Mar 4. [Epub ahead of print]

    [3] Zika Virus Infection in Pregnant Women in Rio de Janeiro – Preliminary Report. Brasil P, Pereira JP Jr, Raja Gabaglia C, Damasceno L, Wakimoto M, Ribeiro Nogueira RM, Carvalho de Sequeira P, Machado Siqueira A, Abreu de Carvalho LM, Cotrim da Cunha D, Calvet GA, Neves ES, Moreira ME, Rodrigues Baião AE, Nassar de Carvalho PR, Janzen C, Valderramos SG, Cherry JD, Bispo de Filippis AM, Nielsen-Saines K. N Engl J Med. 2016 Mar 4. [Epub ahead of print]

    Links:

    Zika Virus (National Institute of Allergy and Infectious Diseases/NIH)

    Microcephaly Information Page (National Institute of Neurological Disorders and Stroke/NIH)

    Hongjun Song (Johns Hopkins University, Baltimore)

    Hengli Tang (Florida State University, Tallahassee)

    NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of Neurological Disorders and Stroke

    http://directorsblog.nih.gov/2016/03/15/zika-and-birth-defects-the-evidence-mounts/

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