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For the first time, abnormal brain development has been documented experimentally following a Zika infection in offspring of a non-human primate.
Researchers' observing how Zika virus stopped fetal brain formation in a pigtail macaque monkey, could become a model for testing therapeutic Zika interventions. Findings are reported Sept. 12 in the advanced online publication of Nature Medicine.
"This is the only direct evidence showing that the Zika virus can cross the placenta late in pregnancy and affect the fetal brain by shutting down certain aspects of brain development," adds study senior author, Michael Gale, Jr., MD and UW professor of immunology. Dr. Gale is an expert on how the body responds to viruses, and directs the UW Medicine Center for Innate Immunity and Immune Disease.
Gale explained that the study results met Koch's Postulate (1884) that there are four criteria to establish a causative relationship between a microbe and a disease: (1) The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms. (2) The microorganism must be isolated from a diseased organism and grown in pure culture. (3) The cultured microorganism should cause disease when introduced into a healthy organism. (4) The microorganism must be reisolated from the inoculated, diseased experimental host and identified as being identical to the original, specific causative agent.
Adams Waldorf, Michael Gale and Lakshmi Rajagopal, all at the University of Washington, Seattle (UW), led the project.
Adams Waldorf: "Our entire team is deeply committed to developing an animal model in which we can rapidly test a vaccine or therapy to determine if we can prevent fetal brain injury caused by the Zika virus."
Primates, including humans, are mammals that share many features of brain development. Non-human and human primates' pregnancies also have key similarities. These include structure of the placenta, timing of nerve and brain development, and the proportions of gray and white matter in the brain.
Previously, no experimental animal model closely emulated the effects of Zika virus infection during human pregnancy. While the virus can cause fetal demise in mice, mouse models have not enabled medical researchers to delve into causal relationships between Zika virus infection and fetal brain injury.
In contrast, the symptoms of a Zika virus infection are often milder. Some people have no symptoms and others develop fever, muscle aches, rash, and sore, swollen eyes. However, contracting the Zika virus during pregnancy is a serious concern, because the fetal brain may be destroyed or quit developing.
The Zika prenatal study took place during the equivalent of the third trimester of a human gestation. The amount of virus inoculated in this study approximated what a person might contract from the probing and biting of an infected, feeding mosquito. The pregnant animal did not show any significant symptoms of infection, such as fever or rash.
The Nature Medicine study listed brain development problems that might affect infants whose mothers had a Zika virus infection during pregnancy. These could include (1) a loss of brain cells and brain cell connections, (2) enlargement of the fluid-containing brain cavities, (3) a smaller-than-normal hindbrain (a part of the brain that controls movement and other functions), and (4) vision problems from disruptions in the optic nerve.
This research conclusively established Zika virus had crossed from the mother through the placenta and into the fetal brain. Gale also pointed out, the viral level in the fetal brain was higher than that in the mother.
Gale also credited the assistance of the Center for Human Immunology and Immunotherapy Programs at Washington University in St. Louis.
The work was supported with funds from the UW Department of Obstetrics and Gynecology and the Washington National Primate Research Center (P51OD010425), and National Institute of Health grants R01AI100989, AI104002, AI083019, AI104002, R01EB017133, R01NS055064, and R01NS061057.
Serial MR images (top), sagittal (middle) and coronal (bottom) of fetal pigtail macaque.
Zika inoculation 10 to 43 days (129–162 days gestation). Scale bar, 40 mm (top).
Red arrowheads indicate T2 hyperintense foci in the bilateral occipital–parietal brain.
Image Credit: Kristina Adams Waldorf MD, Department of Obstetrics and Gynecology,
University of Washington, Seattle, Washington, USA