Study details Zika virus disrupting fetal brain development during pregnancy

For the first time, abnormal brain development following a Zika infection during pregnancy has been documented experimentally in the offspring of a non-human primate. The researchers’ observations of how Zika virus arrested fetal brain formation in a pigtail macaque could provide a model for testing therapeutic interventions.

The 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,” noted Dr. Kristina Adams Waldorf, the lead author of the study. She is a UW Medicine physician and researcher, and a University of Washington professor of obstetrics and gynecology who specializes in maternal and fetal infections.

“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,” she added.

“This is the only direct evidence that shows that the Zika virus can cross the placenta late in pregnancy and affect the fetal brain by shutting down certain aspects of brain development,” said one of the study’s senior authors, Dr. Michael Gale, Jr., UW professor of immunology. An expert on how the body responds to viruses, he directs the UW Medicine Center for Innate Immunity and Immune Disease.

Gale explained that the study results met Koch’s Postulate, which establishes the criteria for determining if a microorganism is a causative agent for a disease or disorder.

Adams Waldorf, Gale and Dr. Lakshmi Rajagopal, UW associate professor of pediatrics, led the project. Rajagopal studies pregnancy and newborn infectious diseases at Seattle Children’s Research Institute and UW Medicine.

“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,” Rajagopal noted. “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.”

She added, “By the time a pregnant woman develops symptoms, the fetal brain may already be affected and damaged.”

“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,” said Adams Waldorf.

Primates, including people, are an order of mammals that share many features of brain development. Non-human and human primates’ gestations also have key similarities. These include the structure of the placenta, the timing of nerve and brain development, and the resulting 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 the causal relationships between Zika virus infection and fetal brain injury.

The Zika virus is transmitted by certain types of mosquitoes, including the Aedes egypti mosquito.

It is a flavivirus, part of a group of insect-carried viruses that cause illness throughout the world. Other mosquito-borne flaviviruses are West Nile virus, Dengue virus, Yellow Fever virus, and the Japanese encephalitis virus. In some cases, those 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 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, a condition where the brain is abnormally small, would have occurred.

The study brought together scientists and physicians from the fields of obstetrics, virology, molecular microbiology, immunology, pediatrics, pathology, radiology, neurology, medicine, bioengineering bioinformatics, neurological surgery, primatology and other fields.

The researchers on the Nature Medicine study listed some brain development problems that could affect some infants whose mothers had a Zika virus infection during pregnancy.

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