Herpes viruses commandeer protein production to storm neurons (Cell Host and Microbe)

By Morgan Kelly, Office of Communications

Viruses in the herpes family most commonly found in humans infect nervous system cells by “turning on” and then seizing control of the internal system these cells rely on to sense injury, among other signaling functions.

Princeton University researchers report in the journal Cell Host and Microbe that the pseudorabies virus (PRV) — a model herpes virus that infects animals — initiates and commandeers protein production in axons, the long offshoots of the cell body that connect neurons to other neurons and to tissue. After entering the neuron at the axon, the virus particles — which deliver the viral DNA that infects host cells — use the newly made proteins to travel to and infect the cell nucleus. Once there, the infection can spread to other neurons.

The research is the latest from the laboratory of senior researcher Lynn Enquist, the Henry L. Hillman Professor in Molecular Biology, to unravel the puzzling efficiency with which PRV and related herpes viruses invade the nervous system. PRV is an alpha-herpes virus, a prolific herpes subfamily that includes herpes simplex virus 1 (HSV-1), an extremely common human virus that causes cold sores and other lesions.

In the current paper, the researchers write that PRV “cleverly exploited” a natural cell process to speed up infection, a theme that resonates in past work from the Enquist lab on alpha-herpes viruses. In 2012, another researcher in the lab reported in Cell Host and Microbe that PRV and HSV-1 infections affect movement of neuronal mitochondria, the mobile organelles that regulate a cell’s energy supply, communication, and self-destruction response to infection.

For this newest research, Enquist worked with lead author Orkide Koyuncu, a postdoctoral research associate in molecular biology, and David Perlman, head of the molecular biology department’s mass spectrometry facility. They suggest that PRV particles first replicate in non-neuronal (such as skin and other tissue) cells at the site of body entry. The particles then enter axon terminals as the axon carries out its regular status-reports with those cells. The process of viral-particle entry is sensed by the neuron as a damage signal, which begins the protein production that will carry the virus particles to the nucleus.

Interestingly, the researchers discovered that the movement of incoming virus particles was disrupted by a genuine damage signal initiated before PRV infection. They hypothesized that the immediate response spurred by injury, infection or inflammation slows down other processes within the axon, which the researchers call “competitive inhibition.” When the molecular details of this crosstalk are fully understood, these signals could be used clinically to prevent the spread of alpha-herpes viruses.

Read the paper.

Citation: Koyuncu, Orkide O., David H. Perlman, Lynn W. Enquist. 2013. Efficient Retrograde Transport of Pseudorabies Virus within Neurons Requires Local Protein Synthesis in Axons. Cell Host & Microbe Vol. 13, no. 1, pp. 54-66.

This work was supported by U.S. National Institutes of Health grant R01NS033506-18.