Breakthrough study discovers mechanism by which Zika virus infects human brain cells

Medical News: Researchers from the University of Cambridge-UK and Institut Pasteur in Paris, France have made a breakthrough in understanding how Zika virus infects human brain cells. The study uncovered a previously unknown mechanism related to specific genes in the virus, known as upstream open reading frames (uORFs), which play a critical role in the virus's ability to grow and spread in the human brain. This Medical News report explains these findings and their implications in simple terms.


Breakthrough study discovers mechanism by which Zika virus infects human brain cells

Zika Virus and Its Effects on the Brain
Zika virus, which is spread by Aedes mosquitoes, was first discovered in Uganda in 1947. However, it wasn't until recent outbreaks in the Americas that Zika became widely recognized as a serious health threat. Most people who contract the virus experience mild symptoms such as fever, rash, and muscle pain. However, in some cases, the virus can cause severe complications, including damage to the brain, particularly in developing fetuses, resulting in conditions like microcephaly, where babies are born with unusually small heads.
 
The virus can also cause Guillain-Barré syndrome, a condition that affects the nervous system, leading to muscle weakness and, in severe cases, paralysis. What makes Zika so dangerous is its ability to infect the developing brain of an unborn baby, leading to congenital Zika syndrome (CZS). The most recognized feature of CZS is microcephaly, but it can also result in other neurological impairments and developmental delays.
 
What Are uORFs and How Do They Work?
In addition to the virus's single long gene, which produces proteins, researchers have found that Zika virus strains also contain smaller gene sequences called upstream open reading frames (uORFs). These sequences were previously unknown in Zika virus strains and can affect how the virus infects human brain cells.
 
The team, led by Dr. Nerea Irigoyen from the University of Cambridge, discovered that the African strain of Zika has one continuous uORF, while the Asian and American strains have two separate uORFs. These uORFs seem to play a critical role in how the virus infects and spreads within the brain.
 
The study used advanced techniques like ribosome profiling, which allows scientists to examine how ribosomes (the cell’s protein factories) interact with viral genes. By doing so, they identified that these uORFs are translated into proteins that influence the virus’s ability to grow and spread, particularly in brain cells. These uORFs could also impact the severity of infections, leading to either less noticeable early abortions or the more visible birth defects seen during the 2015 outbreak in Brazil.
 
The Role of uORFs in Zika Virus Infection
The researchers tested different versions of the Zika virus with changes in their uORFs to see how these affected the virus's ability to infect and grow in human brain cells. They found that uORF1 and the combined African uORF both significantly influenced how well the virus infected human cortical neurons, the cells that make up most of the brain.
 
Interestingly, while these uORFs were present in mosquito cells, they did not seem to affect the ability of mosquitoes to transmit the virus. This suggests that the uORFs play a specialized role in how Zika virus infects humans, especially in brain cells, but not in how mosquitoes carry the virus.
 
Understanding the Brain’s Response to Zika
The study's findings suggest that these uORFs could help explain why Zika virus has such devastating effects on the brain. In human cortical neurons and cerebral organoids (miniature models of the human brain), the presence of these uORFs made the virus more effective at infecting the brain. Without these uORFs, the virus was less able to spread and replicate in these cells, highlighting their importance in the virus's ability to infect brain tissue.
 
The discovery also raises the question of whether other similar viruses, such as dengue or yellow fever, might have similar mechanisms that affect the brain. Understanding these mechanisms is crucial for developing treatments and vaccines that can prevent or minimize the brain-related effects of Zika and related viruses.
 
Insights from Reverse Genetics
To further explore the impact of uORFs, the researchers used a technique called reverse genetics to create versions of the Zika virus with specific changes to these sequences. By observing how these modified viruses behaved in brain cells, they could see that changes in the uORFs affected the virus's ability to grow and spread. Viruses with the African uORF or American uORF1 showed altered growth rates and patterns, particularly in brain cells, suggesting that these small gene sequences have a big impact on the virus's ability to cause disease.
 
One particularly surprising finding was that the virus's ability to affect human neurons didn’t seem to be related to its ability to infect mosquitoes, highlighting the specific role of uORFs in the brain.
 
What Does This Mean for Future Zika Research?
The discovery of uORFs in the Zika virus genome opens up new avenues for research into how the virus causes disease, particularly in the brain. By understanding the role of these small gene sequences, scientists may be able to develop more targeted treatments or vaccines that can prevent the devastating effects of Zika, especially in unborn babies.
 
This research also suggests that other similar viruses could have similar mechanisms that affect the brain, raising important questions about how we understand and treat infections caused by these viruses.
 
Conclusion
In summary, the discovery of uORFs in the Zika virus genome sheds new light on how the virus infects the brain and why it causes such severe damage in some cases. These small gene sequences appear to play a key role in the virus's ability to infect and spread in human brain cells, making them an important focus for future research.
 
By continuing to study these mechanisms, scientists hope to develop better ways to treat and prevent Zika virus infections, particularly in pregnant women and their unborn babies. The potential for similar mechanisms in other viruses also opens up new possibilities for understanding how these viruses affect the brain.
 
The study findings were published in the peer-reviewed journal: Nature Communications.
https://link.springer.com/article/10.1038/s41467-024-53085-9
 
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