Gene finding could yield improved smallpox vaccine

Related tags Smallpox Virus

Scientists studying vaccinia virus, a close relative of smallpox,
have discovered that a gene necessary for virus replication also
plays a key role in turning off inflammation, a crucial antiviral
immune response of host cells.

The discovery could lead to a way of developing improved vaccines against smallpox, which has emerged as a potential bioterrorism threat in the wake of the World Trade Center terrorist attack, despite being eradicated as a naturally occurring disease in 1977. It could also lead to new vaccinia-based vaccines against other pathogens, including HIV.

The discovery, reported this month in the Journal of Virology, potentially broadens the knowledge base of how all poxviruses cause disease and how they may be outwitted by improvements in vaccines against them, said Joanna Shisler, a professor of microbiology at the University of Illinois Urbana-Champaign in the US.

"If we can find out how the virus evades immune responses and learn more about the signals the virus sees as necessary for replicating within the host cell, then we can figure out how to inhibit them and halt the viral replication,"​ she said.

The vaccinia virus genome is 97 per cent genetically identical to the smallpox genome, making it an ideal model virus to use in the laboratory to understand how smallpox and other poxviruses function.

In their research, Shisler and Xiao-Lu Jin, a research specialist in microbiology, found that a 5.2 kb segment of vaccinia virus DNA containing six genes was responsible for inhibiting a key cellular transcription factor called NF kappa B (NF-kB).

NF-kB serves to turn on other host cell genes involved in anti-viral immune responses and inflammation.

The researchers then sought to determine what specific genes in the segment inhibit NF-kB activation. To carry out the study, they introduced individual genes from the 5.2kb segment into a mutant poxvirus vector that activates NF-kB.

They infected human and rabbit cell lines with the new recombinant viruses and detected NF-kB activity levels. This revealed that the recombinant virus containing the introduced K1L gene prevented degradation of the cellular inhibitor of NF-kB, therefore inhibiting NF-kB's ability to ignite immune responses.

Since the 1980s it has been known that K1L is necessary for vaccinia virus replication. The additional function of K1L, as determined in the new study, suggests that poxviruses may need to turn NF-kB on and off at crucial times to regulate replication.

And since this study was completed, the researchers subsequently have found a second protein that inhibits NF-kB, suggesting there may be multiple genes at work, Shisler said.

"These viral proteins are present in smallpox, monkey pox and many other poxes, and they are very homologous,"​ she said. "If we know how these proteins function, we can start figuring out why smallpox and monkey pox cause disease."

Related topics Preclinical Research Ingredients

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