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ScienceWise - Mar/Apr 2009

Mice and men

Article Illustration
Dr Isaac Sakala in his lab. Photo: Karen Edwards

Helping the immune system fight viral infection

Since the dawn of time all animals have been engaged in a life and death struggle with the microorganisms that infect them. To some extent such infectious diseases in humans have been exasperated by the vast social, technological and cultural changes human society has experienced. For example the mass migration to cities during the European industrial revolution was a factor in building deadly cholera and typhoid infections to epidemic levels. In the modern world infectious diseases are still prevalent and are a cause of much human misery especially in developing countries. But fortunately, today we also have advanced science working towards eliminating many of the worst of them.

Dr Isaac Sakala from the John Curtin School of Medical Research is an immunologist working on the Ectromelia virus that causes mousepox, a disease in mice with a very similar pathology to smallpox in humans. Dr Sakala explains, "Ectromelia is a virus from the genus orthopoxvirus and its infection in mice is an excellent model for other medically important orthopoxvirus infections in humans such as smallpox and monkeypox."

Fortunately, the natural threat of smallpox has been eliminated by a worldwide system of vaccination and quarantine, the last recorded case being in 1977. However, Variola virus, the causative agent of smallpox, still exists in two World Health Organisation controlled repositories. There are concerns that Variola virus may fall into the wrong hands and be genetically engineered into a bioterrorism agent. Given that most countries no longer vaccinate against smallpox, the potential death toll from such a release could be horrendous. However, in addition to these man-made threats, there are also new natural sources of orthopoxvirus disease. There has been an increase in monkeypox outbreaks in recent years. Monkeypox has some similarities to smallpox - and worryingly, is impossible to eliminate by vaccination because it can cross between species. Death rates from human monkeypox can be as high as 10% of those infected. For these practical reasons, scientists continue to work towards a better understanding of the orthopoxvirus family and their modes of operation. In a broader context such work is also vital because a better understanding of the workings of the immune system will also help us combat other diseases ranging from tuberculosis to cancer.

During his PhD, Dr Sakala studied the virus-host interaction between mice and the ectromelia virus. During an ectromelia virus infection the virus expresses a molecule that can interfere with the mouse's immune response by binding to a protein known as Interferon-gamma (IFN-g). This reduces the ability of the host to mount an efficient and effective antiviral immune response. In this way the virus is able to effectively protect itself against attack by the immune system. However Dr Sakala believes that understanding this mechanism may give us a means to treat infections. "A better understanding of the role of Interferon-gamma in immunology may give the opportunity for therapeutic intervention. By designing a modified Interferon-gamma that retains its role in immune response but won't bind to the virus blocking receptor, we may be able to greatly improve a patient survival rate even after infection has begun."

Dr Sakala's research has also yielded some surprising results. Generally it has been thought that a host infected with a poxvirus either dies or recovers, eliminating the virus from the body. However, it turns out that ectromelia virus can cause a persistent infection in mice that have a particular genetic makeup. Clearly this has serious implications for eradication of diseases such as human monkeypox. If the same were true of the monkeypox virus in humans, some members of the population who had apparently recovered from the infection may be still able to spread the disease.

Being originally from Zambia, Dr Sakala is more aware of the direct human consequences of viruses than most of us. "From early in my career I've had an interest in the immunology of infectious disease and wanted to work specifically on viruses. Coming from a developing country in which viral infections such as HIV are common, viruses and immunology are very much on my mind."

In recognition of the importance of his recent interferon gamma research Dr Sakala was awarded the prestigious Alan and Elizabeth Finkel Prize in 2008.



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