A Step Forward In Virology - Trojan Horse Of Viruses Revealed

Viruses use various tricks and disguises to invade
cells. ETH Zurich researchers have now discovered yet another strategy
used by viruses: the vaccinia virus disguises itself as cell waste, triggers
the formation of evaginations in cells and is suspected to enter the cell
interior before the immune defense even notices. The research results
have been published in Science.


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
immune
system. This process also has another big advantage: "Viruses cannot
adapt to the obstruction of the signal chain all that quickly", he said.


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, system-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.


ETH Zurich