Direct Evidence for Viral Infection of Neurons

December 15, 2015

The first direct evidence that viruses can infect neuronal cells has been reported, giving more weight to the idea that viral infections may contribute to certain neurologic diseases.

If a causal link can be confirmed, the hope is that it might be possible to use antiviral therapy for diseases such as multiple sclerosis (MS) or Alzheimer's disease or that vaccines could be developed to protect against the development of such diseases, the researchers speculate.

The research, reported online in the journal mBio, an American Society of Microbiology publication, on December 1, shows that Epstein-Barr virus (EBV) and Kaposi's sarcoma–associated herpesvirus (KSHV) can infect and replicate in both cultured and primary neurons.

"We have demonstrated for the first time that a subgroup of herpes viruses can infect human neuronal cells and lead to full-blown infection, which causes death of the neuron and the generation of more viral particles, which can go on to infect other neurological cells and B cells," senior author Erle S. Robertson, PhD, University of Pennsylvania, Philadelphia, commented to Medscape Medical News.

He explained that over the past few years, several reports have described an association between Epstein-Barr virus and neuronal diseases, such as MS and Alzheimer's disease. "Increased titers of the virus have been reported in MS patients. But this has been quite a controversial subject and it has not been known whether there is causal link or not," he added.

Primary neuron at day 5 infection with the Epstein-Barr virus (green). Courtesy of Hem Chandra Jha, PhD, Perelman School of Medicine, University of Pennsylvania

"We have now shown that it is possible for gammaherpes viruses to infect human neuronal cells, which makes it more plausible that Epstein-Barr virus — which is a member of this family — or a similar virus may well be a contributor to neurological diseases."

Causal Link Not Proven

Dr Robertson stressed that this research was at a very early stage, and it is by no means proven that viruses do cause these disease.

"This is the first of many steps that need to be gone through. But our discovery has drawn a direct line between these viruses and neurological diseases. We now need to examine more postmortem tissue samples from Alzheimer's and multiple sclerosis patients to see if we can detect viral gene expression. But if you can infect nerve cells, that's likely to have some sort of pathology," he said.

The experiment was conducted by Devan Mehta, a student in Dr Robertson's laboratory. Using genetically modified viruses that express green fluorescent protein, Mehta infected human neuroblastoma cells (neurons differentiated from cancer cells) and primary human fetal neurons, monitoring the infection over time by microscopy and protein expression.

In both cell types, infection with EBV or KSHV resulted in the appearance of a fluorescent signal in the infected cells, as well as the appearance of key viral proteins. The media in which infected cells were grown also contained functional virus particles capable of infecting other cells, indicating a mode of infection that lyses host cells. In addition, treatment of infected cells with acyclovir reduced the production of virus particles.

In the mBio paper, the researchers write, "for the first time, we have successfully demonstrated the in vitro infection of Sh-Sy5y and Ntera2 cells, as well as human primary neurons. We have also determined that the infection is predominately lytic. Additionally, we also report infection of neuronal cells by KSHV in vitro similar to that by EBV."

They conclude that these findings may open new avenues of consideration related to neuronal pathologies and infection with these viruses, and that their contribution to chronic infection linked to neuronal disease will provide new clues to potential new therapies.

This project was supported by Public Health Service grants to coauthor Erle S. Robertson.

mBio. Published December 1, 2015. Full text


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