virus infection leads to a severe hemorrhagic fever and
presently has no known treatment or vaccine.
involves interaction of viral matrix proteins with host cell proteins
- virus protein interactions promote viral budding from the host cell and
spreads infection to
research has identified a new host-virus interaction that decreases
budding and limits spread of infection.
Novel host cell mechanism to overcome Ebola infection has been identified by a scientists at the
University of Pennsylvania's School of Veterinary Medicine.
The study aimed to investigate interactions between
host and viral proteins in Ebola and other viral infections, and how these
interactions influenced budding of virus and spread of infection to neighboring
cells. Prior studies have revealed that host - virus interactions act to
promote viral budding and spread of infection.
‘Host cell BAG3 (Bcl2-associated athanogene 3) protein could limit the spread of Ebola virus infection by decreasing the rate of virus budding.’
Role of Host- Virus
Infections with Ebola as well and other viruses, such as
Marburg, rabies and HIV, have shown interactions
between viral matrix proteins such as Ebola VP40 with host proteins through
short protein motifs
such as the WW
on the host cell protein and the PY
on the viral protein.
Earlier studies have shown that these interactions promote
viral budding and cause spread of infection within the host.
of Current Study
The research team screened for identifying new WW motifs in
mammalian host cells that were capable of interacting with the corresponding PY
motif of the Ebola Virus
' VP40 protein. Not all viral PY motifs bind to every
WW domain; the binding is specific, comparable to a lock and key.
The screening threw up proteins that the research team had
encountered in prior studies, but additionally they uncovered a new protein
called Bcl2-associated athanogene 3
also referred to as chaperone protein, which normally acts to promote cell
After establishing that the viral protein Ebola VP40 bound
to the full length of BAG3 protein via the WW domain, they went on to assess
how this particular interaction affected viral budding and spread of infection.
During their investigations, the research team employed virus-like particles produced by
the virus's matrix protein, VP40, which are not infectious
copy the budding step of infection.
of the Study
adding BAG3 protein to host cells expressing Ebola or Marburg viral VP40
protein, they found the rate of budding decreased in a dose-dependent manner
of the WW domain of the host BAG3 protein preventing the virus-host
interaction showed the levels of budding to remain unaltered.
naturally occurring levels of BAG3 protein with synthetic strands of RNA
increased the rate of budding.
According to Dr Ronald Harty, a professor of pathobiology
and microbiology at the University of Pennsylvania's School of Veterinary
Medicine, "With all of these assays, there was a consistent effect on
budding levels, either up or down."
the BAG3 Protein Decreased Spread of Ebola Infection
Employing fluorescent labeled proteins and confocal
microscopy, the research team found that the BAG3 protein sequestered VP40 in
the host cell cytoplasm away from the cell membrane where it was critical for
the viral particles to reach in order to be able to bud and spread to other
BAG3 is the first WW containing host protein found to
negatively influence the rate of viral budding.
of the Study
The findings of the study suggest that therapies that
would increase the BAG3 -viral protein interaction, along with other treatments
that might target other stages of the life cycle of the virus could give the
immune system the much needed boost to ward off Ebola infection.
"We think we have uncovered a cellular defense
mechanism against Ebola and other viruses by which the cell can counteract the
virus' ability to bud and spread to other cells," Harty said.
"We want to dissect and understand this interaction
further to potentially mimic the process for use as an antiviral strategy that
could be used to treat these dangerous infections," added
Jingjing Liang, the lead author and a doctoral student at
Guangxi University who had a fellowship at Penn Vet to work in the Harty Lab
for two years.
group plans to conduct more studies
using live Ebola and Marburg
virus. However, they have already shown that BAG3 protein
does reduce viral budding in a recombinant vesicular stomatitis virus that
contains the Ebola PY motif.
Harty's team plan to determine if BAG3 protein just sequesters the VP40 or
affects it in other ways such as causing it to undergo alteration or
While welcoming the news of a successful Ebola virus
vaccine, Dr Harty said, "A vaccine is certainly important, but the
therapeutics are a different arm of the antiviral strategy and are particularly
essential for those who are already infected."
- Jingjing Liang, Cari A. Sagum, Mark T. Bedford, Sachdev S. Sidhu, Marius Sudol, Ziying Han, Ronald N. Harty.Chaperone-Mediated Autophagy Protein BAG3 Negatively Regulates Ebola and Marburg VP40-Mediated Egress. PLOS Pathogens.(2017) http://dx.doi.org/10.1371/journal.ppat.1006132