PA) - In this era of bioterrorism, researchers at the
University of Pennsylvania School of Medicine
have discovered a way to study how smallpox overcomes
the human immune system. Due to the nature of variola,
the virus that causes smallpox, researchers cannot access
the virus conventionally.
Therefore, using previously published data on the DNA
of smallpox, Penn researchers reverse-engineered a variola
protein from vaccinia, a related virus used to vaccinate
against smallpox. Their findings are presented in the
May 28th edition of the Proceedings of the National
Academy of Sciences and suggest new means to develop
safer vaccines and potential therapies for smallpox.
The protein is called the smallpox inhibitor of complement
enzymes, or SPICE for short. SPICE helps smallpox to
elude complement, the collective name for a number of
proteins that serve as the immune system's first line
of defense. SPICE does not cause smallpox itself and
cannot spread the disease. SPICE is only one of several
hundred proteins that contribute to the virus' pathogenesis
and host preference. To understand SPICE's role, the
researchers compared the activity of this protein to
that of human complement regulatory proteins and the
vaccinia virus complement control protein (VCP).
"We have devised a way to study variola without
the risks associated with using the entire virus,"
said Ariella M. Rosengard, MD, an immunobiology
researcher in Penn's Department of Pathology and Laboratory
Medicine. "We need to study variola proteins if
we are to make smallpox less virulent and make the smallpox
vaccine safer. Achieving these goals would be the most
effective way to disarm bioterrorists."
Although smallpox was eradicated over 25 years ago,
clandestine stockpiles of the variola virus are thought
to exist. Their potential use by bioterrorists has prompted
the U.S. Government to increase funding for research
involving the study of anthrax, variola, and other dangerous
pathogens. Variola attacks only humans, and is fatal
in 30 to 40 percent of cases. The only current defense
against smallpox is containment, supportive measures,
and vaccination. Mild and severe side effects were seen
in healthy patients in the era of vaccination.
Then, pregnant women and patients with skin diseases,
such as eczema, were not vaccinated because they were
at much greater risk for severe side effects and death.
Rosengard believes that the risk of side effects from
vaccination may now be even greater.
"The medical climate has changed dramatically since
1977, when smallpox was declared eradicated," said
Rosengard. "Due to the success of modern medicine,
there are more immunosuppressed people than there were
25 years ago. These patients include those with HIV
and those receiving chemotherapy.
Immunosuppressed patients may not be candidates for
the vaccine. This makes it all the more important to
study the virus and create new therapies.".
Rosengard's group molecularly engineered SPICE by an
indirect method, which did not require the virus. They
used the DNA from the homologous vaccinia protein, VCP,
as a template and changed 13 nucleotides to match the
SPICE sequence, which had been published 8 years ago.
This allowed them to produce the protein and study its
"Our research demonstrates that SPICE is nearly
100 times more potent than VCP at inactivating human
complement," said Rosengard. "SPICE's affinity
for human complement also explains why smallpox is so
specific for humans and offers one reason for its virulence."
The complement system defends against infectious microorganisms.
It consists of bloodstream-based enzymes that, when
activated, disable invading microorganisms directly
or serve as beacons for other parts of the immune system,
such as white blood cells. Viruses have evolved complement
regulatory proteins such as SPICE and VCP to distract
human complement in order to allow the virus to slip
Humans also have complement regulatory molecules for
a similar reason: to keep complement from attacking
other human tissues. "Without our own complement
regulators, we'd likely destroy our own cells,"
Since smallpox is specific to humans, Rosengard and
her colleagues became interested in SPICE during their
study of the human complement system. At no time have
any Penn researchers worked with actual variola or native
variola proteins. According to the researchers, DNA
studies have revealed that SPICE is only one of a long
list of genes related to modulating the immune response.
"We hope to have more insight into the pathogenesis
of the virus so that we can disable it and definitively
prevent the spread of smallpox," said Rosengard.
Other Penn researchers involved in this research include
Yu Liu, Zhiping Nie, and Robert Jimenez. Funding for
this research was supported in part by a grant from
the National Institute for Health.
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