How Zika infection drives fetal demise

January 5, 2018, Howard Hughes Medical Institute
When human placental tissue (fluorescence microscopy image shown) is exposed to interferon-β, it develops syncytial knots, which appear as protruding bulges, not seen in healthy tissue. Credit: Yockey et al., Science Immunology (2018)

A powerful antiviral protein may act as a checkpoint for keeping or ending a pregnancy.

When exposed to Zika virus before birth, mouse with the protein commit cell suicide, while fetuses without it continued to develop. The result, published January 5 in Science Immunology, suggests that the protein, a receptor involved in immune cell signaling, plays a role in spontaneous abortions and other human pregnancy complications.

The work could have implications for pregnant women infected with Zika or women with autoimmune disorders who are trying to have a baby, says study author Akiko Iwasaki, a Howard Hughes Medical Institute (HHMI) investigator and immunologist at Yale University.

"Pregnancy is a huge investment for a mother," she says. "Our work shows how this signaling pathway works to terminate pregnancies that are not going to be viable early on."

Zika virus is carried and transmitted by the Aedes aegypti mosquito and can also be spread during sex. Scientists have linked infections during pregnancy to stillbirths and birth defects such as microcephaly, where a baby's head is abnormally small. Iwasaki and other researchers have been studying how signaling proteins called interferons defend the body against the virus.

"Interferons are one of the most potent antiviral factors the body generates," Iwasaki says. When the body detects a virus, cells release interferons, which mount a rapid immune defense. Past studies have shown that adult mice lacking the receptor that binds two types of interferons, -α and interferon-β, are highly susceptible to Zika. But the receptor's effect on infected fetuses was unknown.

In a thick membrane that lines the uterus during pregnancy, cells infected with Zika (purple) secrete type I interferons (blue stars). Fetuses that lack protein receptors that bind interferons continue to develop (IFNAR-/- fetus, left). In contrast, fetuses with the receptors are disturbed by type I interferons, which disrupt the development of the placenta and lead to abnormal blood vessel growth, hypoxia, and fetal death (IFNAR +/-, right). Credit: Akiko Iwasaki & Laura Yockey/ Yale/Howard Hughes Medical Institute

In the new work, Iwasaki and colleagues mated female mice that lacked the receptor with males that had one copy of it. Pregnant mice were then infected with Zika virus. Each female carried a mixture of fetuses that either lacked or had the receptor. Fetuses without the receptor had higher virus levels than those with the receptor. That makes sense, Iwasaki says, because if the receptor is missing, there's no antiviral effect. "The virus can replicate without any control," she says.

But having the receptor didn't guarantee good health. Fetuses with the receptor were aborted early in pregnancy, the team found. A slew of structural and molecular changes may have led to these fetuses' demise. Placentas had underdeveloped blood vessels, the barrier between mother and fetal cells was abnormal, and researchers spotted evidence of cellular stress.

Iwasaki explains that the interferon receptor acts as a checkpoint during pregnancy. If the receptor detects interferons, it can signal molecules that kill the fetus in response. The results suggest that the host's response to the virus is actually what terminates the pregnancy - not the itself.

The team cannot yet say if similar signaling happens in human fetuses infected with Zika. But the researchers wanted to see how interferons might affect human pregnancies. In collaboration with Carolyn Coyne's group at the University of Pittsburgh, Iwasaki's team tested the impact of interferons on human placenta. When exposed to interferon-β, which isn't typically present during a healthy pregnancy, human placental tissue developed abnormal knot structures. Previous studies have linked these structures with high-risk pregnancies. Interferon signaling, and a 's ability to detect and respond to infection, could be tied to adverse pregnancy outcomes in humans, the researchers speculated.

Now, Iwasaki wants to study interferon levels at different time points during pregnancy, which could give clues to how microcephaly and other major health issues associated with Zika develop. But the results are not specific to Zika, Iwasaki says. Interferons also link infections like Toxoplasma, rubella and herpes to pregnancy complications. "We're really excited to see whether the same kind of pathways are also involved in these infections," she says.

This discovery has clinical implications that go beyond viruses, Iwasaki notes. Women with autoimmune diseases, such as lupus, have higher levels of type I interferons. They also have a difficult time with pregnancies. "If we could prevent or treat the interferon response in women with these diseases," she says, " may go better for them."

Explore further: Zika virus may persist in the vagina days after infection

More information: L.J. Yockey el al., "Type I interferons instigate fetal demise after Zika virus infection," Science Immunology (2017). immunology.sciencemag.org/look … 6/sciimmunol.aao1680

Related Stories

Zika virus may persist in the vagina days after infection

August 25, 2016
The Zika virus reproduces in the vaginal tissue of pregnant mice several days after infection, according to a study by Yale researchers. From the genitals, the virus spreads and infects the fetal brain, impairing fetal development. ...

Scientists track Zika virus transmission in mice

August 3, 2017
National Institutes of Health (NIH) scientists have developed a mouse model to study Zika virus transmitted sexually from males to females, as well as vertically from a pregnant female to her fetus. They are using the model ...

Aging impairs innate immune response to flu

December 13, 2017
Aging impairs the immune system's response to the flu virus in multiple ways, weakening resistance in older adults, according to a Yale study. The research reveals why older people are at increased risk of illness and death ...

Zika-related nerve damage caused by immune response to the virus

November 20, 2017
The immune system's response to the Zika virus, rather than the virus itself, may be responsible for nerve-related complications of infection, according to a Yale study. This insight could lead to new ways of treating patients ...

Zika vaccine protects fetus against infection and birth defects

July 13, 2017
Immunizing female mice with a Zika vaccine can protect their developing fetus from infection and birth defects during pregnancy, according to new research from The University of Texas Medical Branch at Galveston. The findings ...

Recommended for you

Thymic tuft cells play key role in preventing autoimmunity, mouse experiments show

July 18, 2018
UC San Francisco researchers were recently surprised to discover fully formed gut and skin cells in the thymus, a lemon-sized organ that sits in front of the heart and is responsible for training the T cells of the immune ...

Autism risk determined by health of mom's gut, research reveals

July 18, 2018
The risk of developing autism-spectrum disorders is determined by the mother's microbiome—the collection of microorganisms that naturally live inside us—during pregnancy, new research from the University of Virginia School ...

New findings suggest allergic responses may protect against skin cancer

July 17, 2018
The components of the immune system that trigger allergic reactions may also help protect the skin against cancer, suggest new findings.

The immune system: T cells are built for speed

July 17, 2018
Without T cells, we could not survive. They are a key component of the immune system and have highly sensitive receptors on their surface that can detect pathogens. The exact way that these receptors are distributed over ...

Broadly acting antibodies found in plasma of Ebola survivors

July 17, 2018
Recent Ebola virus disease (EVD) outbreaks, including the 2013-2016 epidemic that ravaged West Africa and the 2018 outbreak in the Democratic Republic of the Congo, highlight the need for licensed treatments for this often-deadly ...

How protein fragments could help to tackle the cause of hay fever

July 16, 2018
Imperial researchers are looking to protein fragments to help people build up resistance to grass pollen.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.