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Zika brain injury therapy must start at time of bite

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.

"Our results remove any lingering doubt that the Zika virus is incredibly dangerous to the developing fetus and provides details as to how the brain injury develops. This study brings us closer to determining if a Zika vaccine or therapy will prevent fetal brain injury, but also be safe to take in pregnancy."

Kristina Adams Waldorf MD, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, USA, a physician and researcher, Professor of Obstetrics and Gynecology specialist in maternal and fetal infections, and study lead author.

"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.

"We were shocked when we saw the first MRI [magnetic resonance image] of the fetal brain 10 days after viral inoculation. We had not predicted that such a large area of the fetal brain would be damaged so quickly.

"Our results suggest that a therapy to prevent fetal brain injury must either be a vaccine or a prophylactic medicine taken at the time of the mosquito bite to neutralize the virus. By the time a pregnant woman develops symptoms, the fetal brain may already be affected and damaged."

Lakshmi Rajagopal PhD, Associate Professor, Seattle Children's Research Institute and UW Medicine, Center for Global Infectious Disease Research.

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.

Zika is transmitted by certain types of mosquitoes, including the Aedes egypti mosquito. It is a flavivirus in a group of insect-carried viruses that cause illness worldwide.

Other mosquito-borne flaviviruses are West Nile virus, Dengue virus, Yellow Fever virus, and the Japanese encephalitis virus. In some cases, these infections can become complicated by severe nervous system inflammation.

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 white matter of the animal fetal brain, which is important for coordinating communication between different parts of the brain, stopped growing about three weeks after viral inoculation. If the study continued one additional month with the same trajectory of brain growth, microcephaly (where the brain is abnormally small) would have occurred.

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.

They also found the Zika viral genome in fetal eye, liver, and kidneys.

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 could not determine how long the virus stays in the system during pregnancy and fetal development, as the presence of Zika disturbs normal development.

Infection increases growth of supportive structures — and decreases growth of normal nerve cells. This alters brain shape, size and function.

Zika used in this study was a 2010 Cambodian strain almost genetically identical to the Brazilian strain.

The recent ZIKV epidemic in the Americas has been declared a global public health emergency because of its association with severe fetal brain injury during infection of pregnant women. ZIKV is a mosquito-transmitted flavivirus that generally causes a self-limited febrile syndrome characterized by rash, conjunctivitis and arthralgia. However, infection in pregnant women is a major concern because the fetus may develop a range of brain anomalies, including cerebral atrophy, ventriculomegaly, cerebellar hypoplasia and ocular manifestations1. Although ZIKV infection can induce fetal demise in mice2, 3, 4, the lack of an experimental animal model of ZIKV infection that closely emulates human pregnancy has hindered the ability to directly test the causal relationship between ZIKV infection and fetal brain injury5. Here we describe the development of a pregnant pigtail macaque model of ZIKV infection that results in fetal brain lesions. Our results confirm the teratogenic potential of ZIKV and will enable testing of therapeutics to prevent fetal brain injury.

UW Medicine launched the study with the resources and expertise of a well-established team in fetal injury, pregnancy, and infections through the Center for Innate Immunity and Immune Diseases, the Washington National Primate Research Center, the Seattle Children's Research Institute Center for Integrative Brain Research and the Center for Global Infectious Disease Research, and other units.

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.
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Sep 15, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

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



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