Researchers explore how Zika infection causes microcephaly

October 19, 2016, American Society of Human Genetics
Transmission electron microscope image of negative-stained, Fortaleza-strain Zika virus (red), isolated from a microcephaly case in Brazil. The virus is associated with cellular membranes in the center. Credit: NIAID

Infection with Zika virus disrupts fetal brain development by interfering with the proliferation of human neural progenitor cells (hNPCs), a type of cell that drives neurodevelopment and proliferates into brain and nervous system cells, according to research presented at the American Society of Human Genetics (ASHG) 2016 Annual Meeting in Vancouver, B.C.

Understanding Zika's mechanisms will illuminate how viral infection leads to birth defects such as microcephaly, a condition marked by an abnormally small head and brain size, and could inform the development of therapies and vaccines, the study authors said.

"We set out to study why Zika causes microcephaly and related viruses like don't," said Feiran Zhang, PhD, a postdoctoral researcher at Emory University and presenting author on the research. Dr. Zhang and his colleagues at Emory, Johns Hopkins, and Florida State University focused on the effects of the virus in hNPCs, which are highly susceptible to Zika infection. The hNPCs used in this study were derived from healthy skin cells, Dr. Zhang said.

Zika virus was first discovered in Uganda in 1947. Since then, two distinct lineages of the virus have been identified, one African in origin and the other Asian. To compare the effects of each virus on gene expression in these cells, the researchers examined all the messenger RNAs (mRNAs) produced by four groups of hNPCs: cells infected with an Asian strain of Zika virus, cells infected with an African strain of Zika virus, cells infected with a reference strain of dengue virus, and a control group. They found that compared to dengue infection, Zika infection more strongly affects expression of genes involved in DNA replication and repair, processes that are important in brain development.

Interestingly, they found that infection with the Asian strain of Zika virus triggered a stronger innate immune system response than the African strain, including increased expression of the gene TP53. In addition, treatment with p53 inhibitors more strongly inhibited the Asian strain's pathogenicity - its ability to cause harm - than that of the African strain.

"These results suggest that compared to the African strain, the Asian strain's mechanism for causing disease is more dependent on p53," Dr. Zhang explained. He noted that the strain of Zika currently circulating in the Western hemisphere is more similar to the Asian strain than the African one.

In addition to studying mRNA, the researchers also analyzed small RNAs in each group of hNPCs. Both mRNA and small RNAs play important roles in regulating gene expression, Dr. Zhang explained. The researchers observed changes in human small RNAs produced in hNPCs upon Zika infection, as well as in small RNAs directly generated from Zika virus.

Working in laboratory mice, they injected the most abundant of these small RNAs into the mouse brain to assess the impact of each on brain development, including whether they caused microcephaly. They have identified specific small RNAs from Zika virus that could impact brain development and lead to microcephaly, at least in mice.

"Our results suggest that Zika virus might function as a 'Trojan horse' by 'hijacking' the human cell's machinery," Dr. Zhang said. "Once it infects a human cell, the virus could interact with human enzymes to produce these small RNAs, which could in turn alter and lead to microcephaly."

The researchers are now studying which human mRNAs could be regulated by these small RNAs. They hope their findings will inform the development of preventive and therapeutic approaches.

"It's likely that the mechanisms we found are just some of the many ways in which Zika virus acts," Dr. Zhang said. "We want to identify some important pathways in Zika pathogenesis, which we hope will inspire the experts in treatment and vaccine research," he added.

Explore further: Strain differences in Zika infection gene patterns

More information: Dr. Zhang will present his research on Wednesday, October 19, 2016, from 10:15-10:30 a.m., in Room 302 of the Vancouver Convention Centre, West Building.

Related Stories

Strain differences in Zika infection gene patterns

September 1, 2016
Scientists have revealed molecular differences between how the African and Asian strains of Zika virus infect neural progenitor cells.

Research provides clues to how Zika virus breaches the placental barrier

September 15, 2016
New research reveals that in pregnant women, Zika virus infection damages certain cells that affect placental formation and function. Furthermore, herpes simplex virus-2 (HSV-2) infection augments placental sensitivity to ...

Guinea-Bissau Zika cases not from Americas strain: WHO

September 2, 2016
Zika cases found in Guineau-Bissau do not stem from the virus strain linked to a surge in birth defects in Latin America, the World Health Organization said.

Study identifies how Zika virus infects the placenta

August 18, 2016
In a new study, Yale researchers demonstrate Zika virus infection of cells derived from human placentas. The research provides insight into how Zika virus may be transmitted from expectant mother to fetus, resulting in infection ...

Team discovers how Zika virus causes fetal brain damage

August 24, 2016
Infection by the Zika virus diverts a key protein necessary for neural cell division in the developing human fetus, thereby causing the birth defect microcephaly, a team of Yale scientists reported Aug. 24 in the journal ...

Recommended for you

Study reveals how kidney disease happens

February 22, 2018
Monash researchers have solved a mystery, revealing how certain immune cells work together to instigate autoimmune kidney disease.

Past encounters with the flu shape vaccine response

February 20, 2018
New research on why the influenza vaccine was only modestly effective in recent years shows that immune history with the flu influences a person's response to the vaccine.

Building better tiny kidneys to test drugs and help people avoid dialysis

February 16, 2018
A free online kidney atlas built by USC researchers empowers stem cell scientists everywhere to generate more human-like tiny kidneys for testing new drugs and creating renal replacement therapies.

Study suggests expanded range for emerging tick-borne disease

February 16, 2018
Human cases of Borrelia miyamotoi, a tick-borne infection with some similarities to Lyme disease, were discovered in the eastern United States less than a decade ago. Now new research led by the Yale School of Public Health ...

Expanding Hepatitis C testing to all adults is cost-effective and improves outcomes

February 16, 2018
According to a new study, screening all adults for hepatitis C (HCV) is a cost-effective way to improve clinical outcomes of HCV and identify more infected people compared to current recommendations. Using a simulation model, ...

Flu shot only 36 percent effective, making bad year worse (Update)

February 15, 2018
The flu vaccine is doing a poor job protecting older Americans and others against the bug that's causing most illnesses.

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.