Why does Zika virus infect brain cells in fetuses but not adults?

Two studies in EBioMedicine begin to explain the link between Zika and microcephaly in babies

A fetal brain cell line 24 hours after Zika infection. (Image courtesy of Dr. Omar Bagsara)

Since 2015, Zika virus has caused devastation for thousands of families in South America. While infection in adults usually causes no symptoms, if a woman is infected when pregnant the virus can damage brain cells in the unborn fetus. The result has been thousands of cases of microcephaly – a condition in which the baby is born with an abnormally small head and brain.

Widespread fear caused by the link between the Zika virus epidemic and an increase in cases of microcephaly has rippled through South and Central America. For the first time in history, governments have advised women in Brazil and surrounding countries to avoid pregnancy, and suggested pregnant women avoid visiting those countries.

But Zika is relatively harmless to the adults infected with the virus, only causing mild symptoms such as fever, headache, mild rash and joint pain in a minority of cases. Why does Zika virus cause brain defects in developing fetuses and only rarely cause problems in adult brains?

Two studies published in EBioMedicine go some way to explaining this phenomenon, revealing that Zika virus heads straight for stem cells in the brain.

In one study, researchers at Claflin University in the US compared Zika virus infection levels in six different types of brain cell, and in another study, scientists at the Institut Curie, PSL Research University in France compared Zika virus infection to two related viruses that do not cause microcephaly – Dengue and West Nile virus.

Infecting developing brain cells

Zika virus is transmitted by the Aedes mosquito through blood: from mother to fetus and through sexual intercourse. Although it causes no symptoms in most people, it can cause fever, fatigue, headache and muscle and joint pain. In 2015, a serious outbreak in Brazil and neighboring countries was linked to an increase in cases of microcephaly.

In April 2016, the Centers for Disease Control and Prevention (CDC) confirmed that Zika infection during pregnancy can cause microcephaly and other neurological disorders in newborn babies. However, it was unclear why the virus infects fetal brain cells but not the mother’s brain cells.

Alexandre Baffet, PhDDr. Alexandre Baffet of Institut Curie and his colleagues looked at the Zika virus pattern of infection in the mouse brain to understand this. He explained:

In the lab, we investigate brain development as well as how developmental defects can lead to brain malformations, including microcephaly. I recruited a postdoc who had a strong background working with these viruses, and we also teamed up with a virology group at the Institut Pasteur, so we had the perfect combination of skills to ask how virus infection may affect brain development and lead to microcephaly.

To answer these questions, they compared Zika virus infection to two related viruses that do not cause microcephaly – Dengue and West Nile virus. The results revealed that Zika infects stem cells in the brain, altering the way they grow. Dr. Baffet commented:

The effect was really striking – when we infected the tissues with Zika, the virus went straight to the stem cells but only weakly infected neurons. When we first went to the microscope and saw this, we were quite surprised – we didn’t expect something as biased toward stem cells.

Prof. Omar Bagasra, MD, PhDAccording to Dr. Omar Bagsara and his colleagues at Claflin University, Zika virus infects, damages and kills stem cells and partially developed cells much more readily than fully developed adult brain cells.

Dr. Bagsara and his colleagues compared Zika virus infection levels in six different types of brain cell, including stem cells that have not yet developed into neurons. The virus infected up to 90 percent of the stem cells and less than one percent of the adult cells. He commented:

This explains why fetal brain cells are affected, leading to microcephaly in the infant but generally leaving the adult cells unharmed. There is a clear link between Zika virus infection and microcephaly, and we now need to continue studying the infection to understand how this is happening. Stopping this infection is paramount and urgent.

Attacking the epidemic

Indeed, for a relatively recent outbreak, the rise in research and resulting knowledge about Zika virus and microcephaly is exceptional, as Dr. Baffet said:

What is interesting about research on the Zika crisis is how fast the scientific community reacted. There have been lots of papers already, and the field is moving at a very high pace.

This research provides an opportunity to understand the mechanisms of disease and development, potentially unlocking ways to prevent and treat infection. Dr. Bagsara commented:

Unfortunate events and diseases, as sad as they are, bring new insights to human knowledge. We have learned so much from HIV, for example. Similarly, Zika research may bring insight into the dark matter of human brain development.

Dr. Baffet believes cross-disciplinary work can support this:

For us, the collaboration between cell biologists, virologists and neuroscientists has brought together different topics to solve the problem. We can learn a lot about the disease this way, but it can also teach us about how brain develops under non-pathological conditions.

Together, the two papers provide additional evidence for the link between Zika virus infection in pregnant women and microcephaly in babies, revealing that the virus targets stem cells and developing brain cells over adult brain cells – and more than related viruses do. The researchers hope their work will contribute to developing a means to protect against the neurological effects of infection. There is much more to learn and their research continues. Dr. Baffet concluded:

We need to understand the biology of the virus to fight it or treat it. In that sense, our assay is interesting as it helps us see how the virus enters cells and what pathways it affects. We now aim to understand how the virus affects cells on a molecular level, which could help unlock ways of treating infection and preventing cases of microcephaly.

Read the studies

Elsevier has published these articles open access:

The authors

After experiencing life as a Buddhist monk and a Faqir, Dr. Omar Bagasra returned to the University of Karachi in Pakistan, where he earned a bachelor’s and a master’s degree in biochemistry. In 1972, he flew to Chicago, carrying just a suitcase of clothes and an extra hundred dollars in his pocket, eventually earning a PhD from the University of Louisville. He went to study medicine at the Universidad Autónoma de Ciudad Juarez, Mexico. Dr. Bagasra is a diplomat of the American Board of Medical Laboratory Immunology (ABMLI). He currently serves as professor of Biology and the director of the South Carolina Center for Biotechnology at Claflin University. His research interests have long been associated with the study of HIV and AIDS and he currently works on the molecular pathogenesis of Zika virus.

Dr. Alexandre Baffet obtained his PhD in 2011 from the Université Pierre et Marie Curie in Paris, where he worked in the laboratory of Antoine Guichet on the interplay between cell polarity and microtubule network organization in the Drosophila female germline. He then moved to Columbia University in New York, in the lab of Richard Vallee, where he became interested in the development of the mammalian brain, with a strong focus on the neural stem cells. In 2015, he moved back to Paris to establish his group at the Institut Curie in the Department of Cell Biology. He also holds a permanent position at the French institute of health (INSERM). His current research interest concerns neocortex development under normal ad pathological condition. He also focuses on the evolutionary mechanisms underlying human brain expansion.

The journal

With the leadership of Cell and The Lancet, EBioMedicine covers the entire breadth of translational and clinical research within all disciplines of life and health sciences, ranging from basic science to clinical and public/global health science. The journal places a high priority on rapid publication. The journal seeks to publish a broad range of research study types, from experimental findings, critical analyses, methodological & technical innovations, and hypotheses to observational epidemiological studies, clinical trials, meta-analyses, and study protocols. In addition, EBioMedicine publishes commentaries, reviews, and viewpoints that enhance the accessibility and applicability of basic research findings for health professionals, and promote a better understanding of clinical challenges for biomedical researchers.

This journal is published by Elsevier.




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