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.