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Experimental Zika Fetal Brain Disruption Sequence In Non-Human Primate - Nature Medicine

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Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate

http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4193.html

Nature Medicine
 
 
doi:10.1038/nm.4193
Received
 
Accepted
 
Published online
 
Edited by niman

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Author information

  1. Present address: Department of Biology, Calvin College, Grand Rapids, Michigan, USA.

    • Erica Boldenow
  2. These authors contributed equally to this work.

    • Jennifer E Stencel-Baerenwald, 
    • Raj P Kapur, 
    • Colin Studholme, 
    • Erica Boldenow & 
    • Jay Vornhagen

Affiliations

  1. Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, USA.

    • Kristina M Adams Waldorf
  2. Department of Immunology, University of Washington, Seattle, Washington, USA.

    • Jennifer E Stencel-Baerenwald,
    •  
    • Jennifer Tisoncik-Go,
    •  
    • Richard R Green,
    •  
    • Michael A Davis,
    •  
    • Elyse C Dewey,
    •  
    • Marian R Fairgrieve &
    •  
    • Michael Gale Jr
  3. Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA.

    • Jennifer E Stencel-Baerenwald,
    •  
    • Jennifer Tisoncik-Go,
    •  
    • Richard R Green,
    •  
    • Michael A Davis,
    •  
    • Elyse C Dewey,
    •  
    • Marian R Fairgrieve &
    •  
    • Michael Gale Jr
  4. Department of Pathology, University of Washington, Seattle, Washington, USA.

    • Raj P Kapur &
    •  
    • Gwenn A Garden
  5. Department of Pathology, Seattle Children's Hospital, Seattle, Washington, USA.

    • Raj P Kapur
  6. Department of Pediatrics, University of Washington, Seattle, Washington, USA.

    • Colin Studholme,
    •  
    • Erica Boldenow,
    •  
    • Sandra E Juul,
    •  
    • William B Dobyns &
    •  
    • Lakshmi Rajagopal
  7. Department of Bioengineering, University of Washington, Seattle, Washington, USA.

    • Colin Studholme
  8. Department of Radiology, University of Washington, Seattle, Washington, USA.

    • Colin Studholme,
    •  
    • Manjiri K Dighe,
    •  
    • Jeff Thiel,
    •  
    • J Christopher Gatenby,
    •  
    • Todd Richards &
    •  
    • Dennis W W Shaw
  9. Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington, USA.

    • Erica Boldenow,
    •  
    • Jay Vornhagen,
    •  
    • Sean Merillat,
    •  
    • Blair Armistead &
    •  
    • Lakshmi Rajagopal
  10. Department of Global Health, University of Washington, Seattle, Washington, USA.

    • Jay Vornhagen,
    •  
    • Blair Armistead &
    •  
    • Lakshmi Rajagopal
  11. Washington National Primate Research Center, Seattle, Washington, USA.

    • Audrey Baldessari,
    •  
    • Richard F Grant,
    •  
    • LaRene Kuller,
    •  
    • Jason Ogle,
    •  
    • G Michael Gough,
    •  
    • Wonsok Lee &
    •  
    • Chris English
  12. Department of Neurology, University of Washington, Seattle, Washington, USA.

    • Gwenn A Garden
  13. Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Michael S Diamond
  14. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Michael S Diamond
  15. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Michael S Diamond
  16. Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Michael S Diamond
  17. Department of Radiology, Seattle Children's Hospital, Seattle, Washington, USA.

    • Dennis W W Shaw
  18. Department of Neurological Surgery, University of Washington, Seattle, Washington, USA.

    • Robert F Hevner
  19. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.

    • Robert F Hevner &
    •  
    • William B Dobyns

Contributions

K.M.A.W., J.E.S.-B., R.P.K., C.S., M.G. and L.R. designed the study; K.M.A.W., J.E.S.-B., R.P.K., C.S., E.B., J.V., A.B., M.K.D., J.T., S.M., B.A., J.T.-G., M.A.D., E.C.D., M.R.F., J.C.G., T.R., M.S.D., L.K., J.O., G.M.G., W.L., C.E. and L.R. performed the experiments; K.M.A.W., J.E.S.-B., R.P.K., C.S., E.B., J.V., A.B., M.K.D., J.T., R.R.G., S.M., B.A., J.T.-G., M.A.D., E.C.D., M.R.F., J.C.G., T.R., G.A.G., S.E.J., R.F.G., L.K., D.W.W.S., R.F.H., W.B.D., M.G. and L.R. analyzed the data; K.M.A.W., J.E.S.-B., R.P.K., C.S., E.B., J.V., M.K.D., J.T., R.R.G, T.R., M.S.D., D.W.W.S., R.F.H., M.G. and L.R. drafted the manuscript; and all authors reviewed the final draft of the manuscript.

Competing financial interests

M.S.D. is a consultant for Inbios and Visterra, a member of the Scientific Advisory Board of Moderna and OraGene, and a recipient of research grants from Moderna and Visterra. M.S.D.'s activities for these companies may be involved in studies on Zika virus diagnostics, therapeutics or vaccines.

Corresponding authors

Correspondence to: 

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We describe the development of fetal brain lesions after Zika virus (ZIKV) inoculation in a pregnant pigtail macaque. Periventricular lesions developed within 10 d and evolved asymmetrically in the occipital–parietal lobes. Fetal autopsy revealed ZIKV in the brain and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. Our observation of ZIKV-associated fetal brain lesions in a nonhuman primate provides a model for therapeutic evaluation.

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Zika infection causes brain stunting in monkey fetus

GettyImages-453344904-500x500.jpg
PATRIK STOLLARZ/AFP/GETTY IMAGESA pig-tailed macaque climbs a tree in a zoo in western Germany.

For those still skeptical that the Zika virus is causing brain defects in babies infected in the womb, a new study provides some pretty strong evidence.

Researchers from the University of Washington reported Monday that they infected a pregnant pigtail macaque monkey, then monitored the development of her fetus.

Within three weeks of infection, there were already signs that the fetus’s brain had sustained damage. The white matter stopped developing, as did the size of the head.

“We have incontrovertible, irrefutable evidence … that Zika causes fetal brain injury,” lead author Dr. Kristina Adams Waldorf said in an interview with STAT.

“It does it, and it does it fast.”

Adams Waldorf is an obstetrician-gynecologist who researches the impact of infections on pregnancy. While she normally works on bacterial infections, she rapidly shifted gears early this year, gathering a large team of fellow researchers to see if they could study Zika’s effect on developing fetal brains in pigtail macaques — the animal model with which she normally works.

The study, published in the journal Nature Medicine, is unusual, reporting on infection in a single animal. While studies in primates are generally small, it would be more common to have data on three or four infected animals and an equal number of healthy animals for comparison purposes.

Adams Waldorf explained that at the time the group started the trial, they had a single pregnant macaque. So that’s what they studied.

Risks even in late pregnancy

The female was already well-along in her pregnancy, at the equivalent of 28 weeks or the beginning of the third trimester in a human pregnancy. The fetus’s development was monitored by weekly ultrasounds, and it was delivered by Cesarean section at the equivalent of 38 weeks.

In humans, Zika infection in the first trimester seems to lead to the worst damage in affected fetuses. But experts have warned for some time that it’s likely that other problems — hearing loss, vision loss, developmental delays — may arise when infection occurs later in pregnancy.

That’s what this work mirrored, Adams Waldorf said.

The rapidity of fetal brain damage suggests that preventing Zika infection in pregnant women has to be the goal, Adams Waldorf said; developing a treatment to be given after a woman develops symptoms would be a waste of time.

Animal proof?

Adams Waldorf said the work proves Zika infection in the womb causes brain birth defects — fulfilling a test known as Koch’s postulates. Laid out in 1884, Koch’s postulates are criteria that must be met to prove a pathogen causes a disease. A key proof is that the pathogen causes the disease when it is inoculated into a healthy laboratory animal.

Other researchers, though, said one cannot make this claim based on the study of a single animal.

“I think that given what we know about human Zika infection, it’s really tempting to say ‘Aha! This is really showing the same thing in a macaque,’’’ said Dave O’Connor, a professor of pathology and laboratory medicine at the University of Wisconsin-Madison.

“But with [a single animal] and without appropriate controls that were imaged the exact same way at the exact same time points, I would just be a little bit more cautious than that.”

O’Connor has also been working on Zika infection in rhesus macaques, taking the unusual step of sharing his data online in real time. His lab infected four pregnant macaques, but did not see brain damage in the fetuses.

They injected their monkeys with a much lower dose of Zika virus than Adams Waldorf’s team used — another detail that O’Connor and others point to in cautioning how much one can conclude from this experiment.

The monkeys in O’Connor’s lab got one injection of the virus. Adams Waldorf’s team used five injections, each containing 1,000 times more virus than O’Connor used, he noted.

“At best, mosquitoes can deliver a fraction of that,” agreed Nikos Vasilakis, a pathology professor at the University of Texas Medical Branch in Galveston who is also studying Zika infections in macaques.

Adams Waldorf explained that Aedes mosquitoes make a series of small bites when they feed, injecting virus each time if they are infected. That was the rationale for using multiple doses and the amount of virus given to the pregnant animal.

Those issues aside, both O’Connor and Vasilakis praised the work, saying it shows pigtail macaques could be a useful animal model for human Zika infection. Animal models are critical in research, especially in the development of vaccines and drugs.

 

 

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