A step forward in virology

The vaccinia virus has a problem: it is a giant among viruses and needs a special strategy in order to infiltrate a cell and reproduce. Professor Ari Helenius and Postdoc Jason Mercer from ETH Zurich's Institute for Biochemistry have now discovered what this strategy is. In the process, they stumbled upon new and surprising findings.

The invasion strategy

In order to infiltrate a cell, the vaccinia virus exploits the cellular waste disposal mechanism. When a cell dies, other cells in the vicinity ingest the remains, without needing waste disposal experts such as macrophages. The cells recognize the waste via a special molecule, phosphatidylserine, which sits on the inner surface of the double membrane of cells. This special molecule is pushed out as soon as the cell dies and is broken into parts. The vaccinia virus itself also carries this official waste tag on its surface. “The substance accumulates on the shell of vaccinia viruses”, Jason Mercer explained. The pathogen disguises itself as waste material and tricks cells into digesting it, just as they normally would with the remains of dead cells. As the immune response is simultaneously suppressed, the virus can be ingested as waste without being noticed.

The uptake into the cell itself is via macropinocytosis. The ETH Zurich researchers have demonstrated that the vaccinia virus moves along actin-rich filamentous extensions towards the cell. As soon as they impinge upon the cell membrane, an evagination forms, a bleb. The virus itself is the trigger for the formation of the evagination. Using a messenger substance to “knock on the door”, the virus triggers a signaling chain reaction inside the cell so that the bleb forms, catches the virus and smuggles it into the cell.

Proteins as unsuspecting allies

“The viruses are the Trojan horses that want to enter Troy; the Trojans are the many proteins that transmit the signals and open the 'city gates' to the unwelcome guest”, Ari Helenius said. Aided by Professor Lukas Pelkmans' team, Jason Mercer examined over 7000 different proteins in order to find out not only which Trojans let the virus in, but which as well are chiefly involved in the supply chain. Using definitive methods, the researchers de-activated each one of the suspected proteins to examine their function,and narrowed the vast number of proteins down to 140 potential culprits. The enzyme kinase PAK1 turned out to be an especially “helpful” citizen of Troy. Without PAK1, the pathogen's trick did not work and the cell did not form any evaginations.

Until now, very little has been known about the mechanism vaccinia viruses use to infiltrate a cell. Professor Helenius, whose research objective is to find out what methods and strategies various different viruses employ to invade somatic cells, clarified “This strategy is a new one”. Other viruses, such as herpes, adeno and H1 viruses use macropinocytosis. However the vaccinia virus is the first one identified that uses apoptotic mimicry as an entry strategy.

Knowledge of the virus strategies and the signal proteins involved in the ingestion of a virus by a cell is crucial to finding and developing new agents against the pathogens. Until now, antiviral medication has targeted the virus itself. Ari Helenius, however, is looking for substances that interrupt the signaling chain and halt the communication between the virus and the cell. If the cell does not ingest a virus, the virus cannot reproduce and is quickly eliminated by the im-mune system. This process also has another big advantage: “Viruses cannot adapt to the obstruction of the signal chain all that quickly”, he said.

further information:
ETH Zurich
Jason Mercer, Postdoctoral Fellow
Telephone +41 (0)44 632 58 18
jason.mercer@bc.biol.ethz.ch
*
Smallpox: a bioterrorist attack?
The vaccinia virus belongs to a family of particularly dangerous viruses, namely the pox viruses. The most infamous member, Variola, the casitive agent of smallpox constituted a global pandemic disease in the Middle Ages, causing the deaths of millions of people, especially among the indigenous population of North America who became infected by European settlers. Pox was the first viral disease against which a vaccination was developed. In 1771, the first rudimentary vaccine was produced from cowpox viruses, which protected people from the sequelae of the disease. Since 1978, the disease has been classed as eradicated and officially is preserved in only two laboratories; one in Atlanta, the other in Novosibirsk. US authorities, however, fear bioterrorist attacks with pox viruses. Research on these dangerous pathogens is thus encouraged.
*
ETH Zurich (Swiss Federal Institute of Technology Zurich) has a student body of nearly fourteen thousand students from 80 nations. About 360 professors teach mainly in engineering sciences and architecture, systems-oriented sciences, mathematics and natural sciences, as well as carry out research that is highly valued worldwide. Distinguished by the successes of 21 Nobel laureates, ETH Zurich is committed to providing its students with unparalleled education and outstanding leadership skills.