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Zika infection may affect adult brain cells

New research finds Zika a risk to adults and not limited to the fetus. Adult brains may also be vulnerable to infection.

Concern over the Zika virus has focused on pregnant women as evidence suggests it causes brain abnormalities in the developing fetus. However, new research in mice from scientists at Rockefeller University and La Jolla Institute for Allergy and Immunology suggests certain adult brain cells may also be vulnerable. Cells that replace lost or damaged neurons throughout adulthood and are thought to be critical to learning and memory.

"This is the first study looking at the effect of Zika infection on the adult brain. Based on our findings, getting infected with Zika as an adult may not be as innocuous as people think."

Joseph G. Gleeson PhD, Laboratory for Pediatric Brain Diseases, Howard Hughes Medical Institute, The Rockefeller University, New York, and the Department of Neurosciences, Rady Children’s Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA

Although more research is needed to determine if this damage has long-term implications, or potential to affect behavior, currently these findings suggest that Zika may be more harmful than previously believed. The work was published in Cell Stem Cell on August 18.

"Zika can clearly enter the brain of adults and can wreak havoc," says Sujan Shresta, a professor at the La Jolla Institute of Allergy and Immunology. "But it's a complex disease — it's catastrophic to early brain development. Yet, the majority of adults who are infected with Zika rarely show detectable symptoms. Its effect on the adult brain may be more subtle, and now we know what to look for."

Early in gestation, before brains have developed into a complex organ with specialized zones, they are made up entirely of neural progenitor cells. Progenitor cells are more specific than stem cells as they have differentiated into cells targeted for a specific tissue. In healthy individuals, neural progenitor cells can replenish the brain's neurons throughout a lifetime. They eventually become fully formed neurons, and at some point they become resistant to Zika, explaining why adults appear less susceptible to the disease. At least, it is thought that this is what happens.

But current evidence suggests that Zika also targets neural progenitor cells, leading to their loss and reduced brain volume. This closely mirrors what is seen in microcephaly, a developmental condition linked to a Zika infection in developing fetuses resulting in a smaller-than-normal brain and a wide variety of developmental disabilities.

A mature brain retains niches of neural progenitor cells which appear to be particularly impacted by Zika. These niches exist in mice primarily in (1) the subventricular zone of the anterior forebrain and (2) the subgranular zone of the hippocampus, are both vital for learning and memory.

Gleeson's team suspected that if Zika can infect fetal neural progenitor cells, it wouldn't be difficult for them to infect these same cells in adults. In a mouse model engineered by Shresta and her team to mimic Zika infection in humans, fluorescent biomarkers illuminated that adult neural progenitor cells did indeed become hijacked by Zika.

"Our results were pretty dramatic — parts of the brain lit up like a Christmas tree. It was very clear that the virus wasn't affecting the whole brain evenly, as seen in the fetus. In adults, only these two cell populations are affected by the Zika virus. These cells are somehow very susceptible."

Joseph G. Gleeson PhD

Researchers found that Zika infection correlated with evidence of cell death and reduction in new neurons in these two regions. Integration of new neurons into learning and memory is crucial for neuroplasticity which allows the brain to change over time. Deficits in neuroplasticity are associated with cognitive decline in conditions such as depression and Alzheimer's disease.

Gleeson and colleagues recognize that healthy adults may be able to mount an effective immune response and prevent the virus from attacking. However, some people, those with weakened immune systems, may be vulnerable to Zika in a way not yet recognized.

"In more subtle cases, the virus could theoretically impact long-term memory or increase risk of depression," says Gleeson, "but tools do not yet exist to test the long-term effects of Zika on adult stem cell populations."

In addition to microcephaly, Zika has been linked to Guillain-Barré syndrome, a rare condition in which the immune system attacks parts of the nervous system, leading to muscle weakness or even paralysis. "The connection has been hard to trace as Guillain-Barré usually develops after the infection has cleared," says Shresta. "We propose that [ZIKA] infection of adult neural progenitor cells could be the mechanism behind this."

There are still many unanswered questions, including exactly how translatable findings in the mouse model are in humans. Gleeson's findings in particular raise questions. Does the damage inflicted on progenitor cells by the virus have lasting biological consequences, and can this in turn affect learning and memory? Or, do these cells have the capability to recover? Nonetheless, their findings raise the possibility that Zika is not simply a transient infection in adult humans and exposure of the adult brain could have long-term effects.

"The virus seems to be traveling quite a bit as people move around the world. Given this study, I think the public health enterprise should consider monitoring for Zika infections in all groups, not just pregnant women."

Joseph G. Gleeson PhD

Abstract Highlights
•Zika virus (ZIKV) can infect neural progenitors in the adult mouse brain
•ZIKV-infected adult NPCs show evidence of cell death
•Cell proliferation is also impacted in ZIKV-infected adult NPC populations

Zika virus (ZIKV)-related neuropathology is an important global health concern. Several studies have shown that ZIKV can infect neural stem cells in the developing brain, but infection in the adult brain has not been examined. Two areas in the adult mouse brain contain neural stem cells: the subventricular zone of the anterior forebrain and the subgranular zone of the hippocampus. Here, using 6-week-old mice triply deficient in interferon regulatory factor (IRF) as a model, we show that blood-borne ZIKV administration can lead to pronounced evidence of ZIKV infection in these adult neural stem cells, leading to cell death and reduced proliferation. Our data therefore suggest that adult as well as fetal neural stem cells are vulnerable to ZIKV neuropathology. Thus, although ZIKV is considered a transient infection in adult humans without marked long-term effects, there may in fact be consequences of exposure in the adult brain. Keywords: adult neurogenesis, Zika virus, interferon, neural progenitor cells

Joseph Gleeson also holds appointments at the University of California San Diego School of Medicine and Rady Children's Hospital-San Diego.

About The Rockefeller University
The Rockefeller University is the world's leading biomedical research university and is dedicated to conducting innovative, high-quality research to improve the understanding of life for the benefit of humanity. Our 79 laboratories conduct research in neuroscience, immunology, biochemistry, genomics, and many other areas, and a community of 1,800 faculty, students, postdocs, technicians, clinicians, and administrative personnel work on our 14-acre Manhattan campus. Our unique approach to science has led to some of the world's most revolutionary and transformative contributions to biology and medicine. During Rockefeller's 115-year history, 24 of our scientists have won Nobel Prizes, 21 have won Albert Lasker Medical Research Awards, and 20 have garnered the National Medal of Science, the highest science award given by the United States.

About La Jolla Institute
La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading towards its goal: life without disease®.
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Aug 23, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Current evidence suggests that Zika targets adult neural progenitor cells, leading to loss
of these cells and to reduced brain volume. This closely mirrors what is seen in microcephaly,
a condition linked to Zika infection in developing fetuses.
Image Credit: Joseph Gleeson, Rockefeller University



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