May 28, 2002 (Philadelphia, 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 function.
“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 past. 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,” said Rosengard.
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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