In a healthy neuron (left), mitochondria are carried along by motor proteins dynein and kinesin-1. Viral infection (right) floods the cell with calcium (Ca2+), which, when detected by the mitochondrial protein Miro, brings mitochondria to a halt and causes them to shed motor proteins. The Princeton researchers suggest that the virus then co-opts kinesin-1 to freely move within the infected cell and spread into the nervous system. The research presents a possible explanation for how other neurotropic viruses such as rabies, West Nile and polio also attack and disrupt the nervous system. (Image by Tal Kramer.)
Herpes and other viruses that attack the nervous system may thrive by disrupting cell function in order to hijack a neuron’s internal transportation network and spread to other cells.
Princeton University researchers made the first observation in neurons that common strains of the herpes virus indirectly take control of a cell’s mitochondria, the mobile organelles that regulate a cell’s energy supply, communication with other cells, and self-destruction response to infection. The team reports in the journal Cell Host and Microbe that viral infection elevates neuron activity, as well as the cell’s level of calcium — a key chemical in cell communication — and brings mitochondrial motion to a halt in the cell’s axon, which connects to and allows communication with other neurons.
The authors propose that the viruses then commandeer the proteins that mitochondria typically use to move about the cell. The pathogens can then freely travel and reproduce within the infected neuron and more easily spread to uninfected cells. When the researchers made the mitochondria less sensitive to calcium the viruses could not spread as quickly or easily.
These findings reveal a previously unknown and highly efficient mechanism that some of the most common strains of herpes viruses in humans may use to proliferate in the nervous system, said lead author Tal Kramer, a doctoral student in the lab of the paper’s co-author Lynn Enquist , the Henry L. Hillman Professor of Molecular Biology and chair of Princeton’s molecular biology department.
Kramer and Enquist used rat neurons to study two herpes viruses in the alpha-herpes virus subfamily: pseudorabies virus (PRV), a model alpha-herpes virus that infects animals, and herpes simplex virus 1 (HSV-1), an extremely common human virus that causes cold sores and other lesions. Other human alpha-herpes viruses are responsible for causing diseases such as chicken pox and shingles.
"No one before has looked carefully at mitochondrial motion during alpha-herpes virus infection in neurons. We provide new insight into how these viruses damage cells in the nervous system in ways that are important for the virus to propagate," Kramer said.
"If mitochondria are stopped in their tracks and can’t go anywhere, that is potentially very bad," he said. "They are not only the power plants of the cell, but regulate important processes. The virus likely acts to interfere with many of those processes."
Princeton University researchers made the first observation in neurons that common strains of herpes thrive by hijacking the transportation of a cell’s mitochondria, which regulate a cell’s energy supply, communication with other cells, and self-destruction response to infection. Using live-cell imaging, the Princeton researchers observed that pseudorabies virus — a model herpes virus that infects animals — stopped all mitochondrial motion in rat neuron axons, which connect to and allow communication with other neurons. The researchers saw similar results with herpes simplex virus 1, a sexually transmitted infection that is extremely common in humans and causes cold sores and other lesions. Both viruses belong to the herpes subfamily alpha-herpes viruses, which includes the viruses that cause diseases such as chicken pox and shingles. (Video by Tal Kramer)
Beyond herpes, the Princeton findings present a possible explanation for how other neurotropic viruses such as rabies, West Nile and polio attack and disrupt the nervous system, Kramer said. Although these viruses are different from the herpes family, the fact that HSV-1 and PRV had a similar effect on mitochondrial motion and function suggests that other pathogens could corrupt mitochondria in the same way, he said.
In addition, the paper lays out the implications of distorted mitochondrial function on neuron health. Mitochondrial malfunction is a known factor in non-infectious neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease, Kramer said, though the pathway to this disruption is not entirely known.
"Our model raises some new and exciting possibilities for future research on other important human viruses that can invade the nervous system and cause disease," Kramer said.
"And the fact that alpha-herpes infection damages the same key cellular function as neurodegenerative disorders also is striking," he said. "Understanding how viral infection damages neurons might give us insight into how diseases like Alzheimer’s do the same. The viruses we study hijack well-studied cellular pathways that might make an effective target for future therapeutic strategies."
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