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Brazilian Zika causes birth defects in mice - Nature

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niman Grand Master

niman

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  • Author
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  • Fernanda R. Cugola,
  • Isabella R. Fernandes,
  • Fabiele B. Russo,
  • Beatriz C. Freitas,
  • João L. M. Dias,
  • Katia P. Guimarães,
  • Cecília Benazzato,
  • Nathalia Almeida,
  • Graciela C. Pignatari,
  • Sarah Romero,
  • Carolina M. Polonio,
  • Isabela Cunha,
  • Carla L. Freitas,
  • Wesley N. Brandão,
  • Cristiano Rossato,
  • David G. Andrade,
  • Daniele de P. Faria,
  • Alexandre T. Garcez,
  • Carlos A. Buchpigel,
  • Carla T. Braconi,
  • Erica Mendes,
  • Amadou A. Sall,
  • Paolo M. de A. Zanotto,
  • Jean Pierre S. Peron,
  • Alysson R. Muotri
  • & Patricia C. B. Beltrão-Braga

  • Affiliations

    1. University of São Paulo, Department of Surgery, Stem Cell Laboratory, São Paulo, São Paulo 05508-270, Brazil

      • Fernanda R. Cugola,
      •  
      • Isabella R. Fernandes,
      •  
      • Fabiele B. Russo,
      •  
      • João L. M. Dias,
      •  
      • Katia P. Guimarães,
      •  
      • Cecília Benazzato,
      •  
      • Nathalia Almeida,
      •  
      • Graciela C. Pignatari &
      •  
      • Patricia C. B. Beltrão-Braga

    2. University of California San Diego, School of Medicine, Department of Pediatrics/Rady Children’s Hospital San Diego, Department of Cellular & Molecular Medicine, Stem Cell Program, La Jolla, California 92037-0695, USA

      • Isabella R. Fernandes,
      •  
      • Beatriz C. Freitas,
      •  
      • Sarah Romero &
      •  
      • Alysson R. Muotri

    3. Tismoo, The Biotech Company, São Paulo, São Paulo 01401-000, Brazil

      • Fabiele B. Russo &
      •  
      • Graciela C. Pignatari

    4. University of São Paulo, Department of Immunology, Neuroimmune Interactions Laboratory, São Paulo, São Paulo 05508-000, Brazil

      • Carolina M. Polonio,
      •  
      • Isabela Cunha,
      •  
      • Carla L. Freitas,
      •  
      • Wesley N. Brandão,
      •  
      • Cristiano Rossato,
      • David G. Andrade &
      •  
      • Jean Pierre S. Peron

    5. University of São Paulo, Department of Radiology and Oncology, USP School of Medicine, São Paulo, São Paulo 05403-010, Brazil

      • Daniele de P. Faria,
      •  
      • Alexandre T. Garcez &
      •  
      • Carlos A. Buchpigel

    6. University of São Paulo, Department of Microbiology, Institute of Microbiology Sciences, Laboratory of Molecular Evolution and Bioinformatics, São Paulo, São Paulo 05508-000, Brazil

      • Carla T. Braconi,
      •  
      • Erica Mendes &
      •  
      • Paolo M. de A. Zanotto

    7. Institute Pasteur in Dakar, Dakar 220, Sénégal

      • Amadou A. Sall

    8. University of São Paulo, School of Arts, Sciences and Humanities, Department of Obstetrics, São Paulo, São Paulo 03828-000, Brazil

      • Patricia C. B. Beltrão-Braga

    Contributions

    F.R.G. derived the NPCs, neurons and neurospheres, performed the viral infections and cell analyses and analysed the data. I.R.F. performed the viral infections of cells, processed and analysed infected brain organoids, prepared manuscript figures and analysed the data. F.B.R. derived the NPCs, performed immunostainings and analyses, prepared manuscript figures and analysed the data. B.C.F. revised the manuscript and with S.R. generated the organoid cultures from iPSCs and assisted with the immunofluorescence staining and experimental design. J.L.M.D. performed macroscopic and microscopic staining and analyses of the mice. K.O.P.G. performed the TEM experiments, RNA extraction and quantification and histopathological analyses. C.B. and N.S. performed RNA extraction and quantification and prepared figures. G.C.P. performed cell cultures, analysed the data and revised the manuscript. C.M.P., I.C., C.L.F., W.N.B. and C.R. performed cell death qPCR assays and flow cytometry, D.G.A performed flow cytometry staining protocols and analysed the data. C.M.P., I.C. and D.G.A. infected and observed the pregnant mice daily. C.M.P., C.L.F., I.C. and C.R. processed the mouse tissues for virus quantification and further analyses. D.P.F., A.T.G. and C.A.B. performed the CT scans and analysed and plotted the data. C.T.B. and E.A.M. performed virus amplification, titration and gene expression analysis. A.A.S. provided MR766 and YFV-17D isolates and serological reagents. P.M.A.Z. designed the experiments and revised the manuscript. J.P.S.P., A.R.M. and P.C.B.B.-B. designed the experiments, analysed the data and wrote the manuscript.

    Competing financial interests

    The authors declare no competing financial interests.

    Corresponding authors

    Correspondence to: 

niman Grand Master

niman

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Zika virus (ZIKV) is an arbovirus belonging to the genus Flavivirus (familyFlaviviridae) and was first described in 1947 in Uganda following blood analyses of sentinel Rhesus monkeys1. Until the twentieth century, the African and Asian lineages of the virus did not cause meaningful infections in humans. However, in 2007, vectored by Aedes aegypti mosquitoes, ZIKV caused the first noteworthy epidemic on the Yap Island in Micronesia2. Patients experienced fever, skin rash, arthralgia and conjunctivitis2. From 2013 to 2015, the Asian lineage of the virus caused further massive outbreaks in New Caledonia and French Polynesia. In 2013, ZIKV reached Brazil, later spreading to other countries in South and Central America3. In Brazil, the virus has been linked to congenital malformations, including microcephaly and other severe neurological diseases, such as Guillain–Barré syndrome4, 5. Despite clinical evidence, direct experimental proof showing that the Brazilian ZIKV (ZIKVBR) strain causes birth defects remains absent6. Here we demonstrate that ZIKVBR infects fetuses, causing intrauterine growth restriction, including signs of microcephaly, in mice. Moreover, the virus infects human cortical progenitor cells, leading to an increase in cell death. We also report that the infection of human brain organoids results in a reduction of proliferative zones and disrupted cortical layers. These results indicate that ZIKVBR crosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death by apoptosis and autophagy, and impairing neurodevelopment. Our data reinforce the growing body of evidence linking the ZIKVBR outbreak to the alarming number of cases of congenital brain malformations. Our model can be used to determine the efficiency of therapeutic approaches to counteracting the harmful impact of ZIKVBR in human neurodevelopment.

niman Grand Master

niman

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Zika

This sonogram shows a rhesus macaque fetus 25 days after being infected.

Sarah Kohn/Kathleen Antony/Saverio Capuano/Jennifer Post

Zika causes microcephaly in mice

By Jon Cohen

By far the most alarming feature of the Zika virus now marching across South America and the Caribbean is its threat to fetuses. Last month the U.S. Centers for Disease Control and Prevention declared that “a causal relationship” exists between the virus and brain abnormalities in newborns—most noticeably a small head, known as microcephaly. But just how a mother’s infection harms the fetus, and how to prevent the damage, is uncertain.

New animal models are now pointing to answers. Pregnant monkeys are showing hints of fetal damage. But the most dramatic results come from mice. Mouse studies published this week in Cell and its sister journal Cell Stem Cell and in Nature show precisely how the virus slows fetal growth, damages the brain, and leads to miscarriage. Two of them also prove for the first time in an animal model that Zika virus can cause microcephaly in fetuses.

Together, the findings indicate that the virus by itself can wreak havoc, says Michael Diamond, a viral immunologist at Washington University in St. Louis in Missouri who led the Cell study. “Some people feel there are many cofactors like insecticides,” Diamond says. “Our study suggests at least you don’t have to invoke other things.” And by providing an animal model for the fetal damage, the studies should also ease the path for testing potential vaccines and treatments.

Mice normally cannot sustain a Zika infection because the virus triggers secretion of interferons, molecules that bolster immune responses. Diamond’s lab circumvented this problem by creating female mice that had a key interferon gene knocked out; in a second experiment, they treated pregnant animals with an anti-interferon antibody. The team then injected pregnant females with a virus isolated from a person in French Polynesia; the isolate is 99% genetically similar to the one now circulating in Latin America.

In the knockout mice, the virus replicated to higher levels than in those treated with the antibody, killing most of the fetuses. The researchers found high levels of Zika virus in the placentas—1000 times more than in the mother’s blood—supporting the hypothesis that the virus harms the placenta, which, in turn, cuts the blood supply to the fetus, Diamond says.

Pregnant mice treated with the antibody still made enough interferon to partially control the infection and allow the pups to survive. Mirroring effects seen in humans, they were born small, a condition known as intrauterine growth restriction.

In both sets of mice, the virus also turned up in fetal heads, Diamond says, suggesting that it causes brain damage directly as well as by impairing the placenta. That’s consistent with earlier in vitro findings that Zika can infect and damage human neural precursor cells. Neither set of pups developed microcephaly, which Diamond says could be because the researchers infected the mothers so early during pregnancy that not much brain development had yet occurred.

The two other mouse experiments, published in Cell Stem Cell and Nature, did document microcephaly. Neither team manipulated their mice to make them more susceptible to the virus. In the Cell Stem Cell study, Zhiheng Xu of the Chinese Academy of Sciences in Beijing sidestepped the mice’s natural resistance to Zika virus by injecting a Samoan isolate directly into fetal brains. In Nature, Fernanda Cugola of the University of São Paulo in Brazil and co-workers injected a Brazilian isolate into the tails of a strain of mice that are naturally immunocompromised. Diamond notes that the Brazilian-led team injected an “astronomical amount of virus” through the intravenous route, which may have sent the virus directly to the placenta and helped dodge the antiviral immune response.

Both studies found malformations associated with microcephaly, including what’s known as cortical thinning and smaller brains. The two reports also showed that Zika virus infected and damaged neuronal stem cells harvested from mice and humans. “If you see consistent phenotypes in different models, the things that are happening are probably important,” says Guo-li Ming of Johns Hopkins University School of Medicine in Baltimore, Maryland, who led the earlier studies of Zika in human neural progenitor cells.

The researchers who study these various mouse models acknowledge that they differ from humans in many critical ways. “It’s very difficult to study humans directly,” Diamond notes. Yet he stresses that these mouse models give insights into pathogenesis and will allow for high-throughput screening of drugs and vaccines against the virus.

Zika

Pregnant mice engineered to have higher levels of Zika virus had smaller fetuses (top) than normal dams (bottom).

Miner et al., Cell165, (19 May 2016)

Monkeys are naturally infected with Zika virus and are far closer to humans in many ways, and at least a half-dozen studies are underway. In an unusual twist for the primate research community, investigators from four U.S. labs have been posting data from their monkey Zika experiments on their websites in near real time, before publication. “We decided that the best thing for the community was that information be made available as widely as possible and freely available,” says David O’Connor, whose group at the University of Wisconsin, Madison, is furthest along in studying Zika infection of pregnant monkeys.

One pregnant rhesus macaque that O’Connor’s group is following was 50 days postinfection at last report, and a little more than halfway through her pregnancy. Sonograms of the fetus—which are posted online—“sort of” show evidence that the head circumference is small, but O’Connor and colleagues “are not drawing too much attention to it,” he says, because it’s not that far outside of the normal range. The group will know for sure after they perform a cesarean section on the mother—which will also let them obtain the placenta, normally eaten by rhesus mothers. “I hope we can accelerate the information about what’s going on in people,” he says.

O’Connor points out that Zika-infected monkeys do not perfectly reflect humans, either, and he sees the various models as complementary. “We can learn a lot from the fact that pregnancies are quick in the mice and you can do much larger experiments, but in monkeys we can do experiments that are much more relevant to human pregnancy,” he says. “Clearly, we have a lot of work to do, but these experiments are opening up the possibility that Zika’s effects during pregnancy may be much more common than we initially thought.” 

niman Grand Master

niman

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How The Zika Virus Damages The Brain

Heard on All Things Considered
This 3-month-old baby, born with microcephaly, is held by her father in Recife, Brazil.

This 3-month-old baby, born with microcephaly, is held by her father in Recife, Brazil.

Mario Tama/Getty Images

A few weeks ago, Dr. James Bale saw a series of MRI images in a medical journal of MRI scans of babies infected with Zika in the womb.

They scans showed something Bale had seen only a few times in his 30-year career: a phenomenon called fetal brain disruption sequence.

As the fetus's brain starts to grow, it creates pressure, which pushes on the skull and causes it to grow. But if something stops brain growth — such as a virus — pressure on the skull drops. And the skull can collapse down onto the brain.

The skin around the head continues to grow, Bale says. So the baby is born with wrinkles of skin at the back of the neck and a tiny skull. In some cases, the baby's head is as small as an orange, or about half the size of a healthy baby's head.

"It's quite remarkable what the Zika virus is doing to the brain of young infants," Bale says. "Many of them will die often in infancy, and the majority, if not all, will then have a long-term, severe developmental problems."

Now scientists think they have an understanding about how Zika causes these severe brain malformations. The findings come from a series of mouse experiments, published Wednesday in three leading journals.

In one study, published in Nature, Alysson Muotri and his team at the University of California, San Diego, infected pregnant mice with Zika and looked to see how the virus harmed the baby mice.

"We detected the virus all over the mice and in different regions of the body," Muotri says.

But for some reason — and scientists don't know why yet — Zika is particularly attracted to brain cells. And once inside the cells, Muotri says, Zika turns them into viral factories that start producing huge amounts of virus. Until they burst.

"They explode, and more viral particles are released that can infect other cells. And they can just amplify themselves," Muotri says.

More and more brain cells get infected. More die. This cell death is already a problem for the fetus. It scars the brain and creates inflammation.

But the situation gets worse because the brain cells infected by Zika are extremely special. They're called neural progenitor cells. And they're responsible for building a large portion of the brain.

"These are fast-replicating cells that will give rise to billions of cells in our brains," Muotri says.

So if a fetus loses even just a small percentage of these cells, a portion of its brain will never develop. "And the impact later in life would be dramatic," he says.

A second study, published in the journal Cell Stem Cell, confirmed that Zika destroys neural progenitor cells inside a growing embryo. In that experiment, a team of scientists at the Chinese Academy of Sciences, injected the virus directly into the brains of mice embryos, developing inside their moms.

Muortri says death of brain cells is likely the major way that Zika causes microcephaly in babies. But it isn't the full picture.

In the third study, Indira Mysorekar and her colleagues at Washington University in St. Louis, also infected pregnant mice with Zika.

They found the virus not only damages the brain but also attacks the placenta.

"The nutrient and blood exchange that normally happens between the mother and the fetus is reduced," Mysorekar says. This slows down the baby's growth — and may hurt the brain as well.

Mysorekar and her colleagues published their findings in the journal Cell.

She says mouse experiments can never tell us exactly what's happening in people. Human anatomy is more complicated.

But one thing is clear: Once Zika infects the fetus, "it leaves a lot of havoc and devastation in its wake," she says. "It's almost like a tornado or an earthquake. There is death following Zika."

http://www.npr.org/sections/goatsandsoda/2016/05/11/477648872/how-the-zika-virus-damages-the-brain

 

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