YSM Issue 93.2

NEWS
Biochemistry
THE DUALITY
OF THE
EBOLA VIRUS
How a Deadly Viral Infection
Can Be Harnessed for Healing
BY SYDNEY HIRSCH IMAGE COURTESY OF FLICKR
When we hear “Ebola,” we often think of its contagion and
lethality, and of the outbreaks in recent years. Ironically,
scientists are exploring the potential of the deadly Ebola
virus (EBOV) as a treatment against a fatal form of cancer: brain
tumors. Cancer cells lack the ability to generate an immune response
against viruses, making viruses a good starting point for developing
treatments. Of course, infecting someone with a lethal virus is risky; to
circumvent this, scientists use chimeric viruses, which contain a mix of
genes from multiple parent viruses. A team of researchers, including
Yale professor Anthony Van den Pol, recently reported their efforts to
test three variations of a chimeric virus, pairing an EBOV glycoprotein
with the vesicular stomatitis virus (VSV). They chose the Ebola gene,
given the virus’s propensity to infect—and for their purposes, target—
nerve tissue. Specifically, they took interest in the mucin-like domain
(MLD) of the Ebola virus, and how it modulates the viral ability to
target brain tumors. Interestingly, it seemed as if the MLD protected
normal cells from infection, while cancer cells still became infected.
They were hopeful that VSV-EBOV could be a promising treatment,
as the combination had been an effective and safe vaccine in humans
during the African Ebola outbreak.
The team tested three viruses on severe combined immunodeficient
(SCID) mice, which had human brain tumor cells injected into their
brains: VSV-EBOV, which contains the mucin-like domain (MLD);
VSV-EBOVΔMLD, which is a parallel construct but lacks the mucinlike
domain; and VSV-EBOVΔMLD-GFP, which is almost identical
to VSV-EBOVΔMLD with an added green-fluorescent protein (GFP)
reporter gene to visualize a virus. All three showed some increase in
the mice’s survival. The researchers found that the VSV-EBOV was
most effective in treating the brain tumors while maintaining the
health of the mouse. At 120 days after the tumor implant, only mice
infected with the MLD-containing virus remained alive.
The researchers considered VSV-EBOV successful because it
minimally infected healthy neural cells while still targeting tumor
cells. Van den Pol’s team quantified the extent of the brain infection
by counting the number of infected neurons and glial cells in coronal
brain sections. The other two virus forms showed widespread infection
throughout the brains of the animals. The VSV-EBOVΔMLD-GFP was
the least effective. While it modestly extended the survival of the mice,
all of the mice died. Some were incompletely infected by the virus, and
many still had brain tumors. The VSV-EBOVΔMLD injected tumors
had similar tissue structure, and a greater survival rate.
The lethality of the VSV-EBOVΔMLD-GFP virus may have been
due to the VSV backbone itself; this differs from those of the non-
GFP chimeric viruses in all four of their base proteins, which may
alter the behavior of the virus. Van den Pol explained that the Ebola
virus may release the MLD as a “false leader, causing the immune
system to be lured away from the infected cells.” This slowed
replication of the virus and lessened the amount of infectious viral
offspring. With a slower replication rate, the innate immune system
has more time to upregulate antiviral defenses. The low number of
infected normal cells suggested that the innate immune system was
sufficient to prevent the spread of the virus.
Researchers also compared the effects of intravenous versus
intracranial injection. Both methods had degrees of success.
Intracranial injection showed greater tumor infection and elimination,
indicating this type of delivery may be more reliable for treating larger
tumors. Intravenous injections, which are done through the tail-vein
in mice, could on the whole be more effective for smaller or undetected
types of metastatic cancer, such as melanomas.
Van den Pol and his team were able to monitor the impact of the
MLD on the treatment and survival of SCID mice. The chimeric
virus containing the mucin-like domain, VSV-EBOV, was the most
successful treatment, confirming their initial expectations. This
research is promising, as it could open the door for new forms of
glioblastoma treatment. “VSV-EBOV has been successfully used in
the human population in the past, showing that it’s relatively safe. If
we’re ultimately trying to move toward clinical studies, that’s a hurdle
already jumped over,” Van den Pol said. Future directions include
looking at tumors in immunocompetent mice or exploring other
VSV-based viruses. ■
Zhang, X., Zhang, T., Davis, J.N., Marzi, A., Marchese, A.M., Robek,
M.D., & van den Pol, A.N. (2020). Mucin-Like Domain of Ebola
Virus Glycoprotein Enhances Selective Oncolytic Actions against
Brain Tumors. Journal of Virology, 94(8), e01967-19.
8 Yale Scientific Magazine September 2020 www.yalescientific.org