A team of scientists led by a Howard Hughes Medical Institute (HHMI) international research scholar has discovered the immune system mechanism that causes some mice to be more susceptible to mousepox than others.

HHMI international research scholar Gunasegaran Karupiah, a scientist at the John Curtin School of Medical Research at the Australian National University, and colleagues have identified proteins that determine which mice succumb to mousepox and which do not.

The discovery could pave the way to better protection for humans against the threat of smallpox, a related virus, as a weapon of bio-terrorism.

The new insights into the immune response of mice to the mousepox virus could enable scientists to combine antivirals and cytokines such as gamma interferon to increase the efficacy of the treatment of poxvirus infections, including smallpox, said Karupiah.

The researchers found that strains of mice that are resistant to mousepox infection generate three types of the regulatory proteins called cytokines that are released by immune system cells to produce an immune response, interferon gamma (IFN-g), interleukin-2 (IL-2), and tumour necrosis factor (TNF). Collectively, this is known as a type-1 cytokine response. Strains of mice susceptible to infection produce little or none of these cytokines, but they do produce IL-4-a type 2 cytokine.

A potentially important application could be treating or protecting the increasing numbers of persons being vaccinated against smallpox with the vaccinia virus-primarily health professionals in the United States and elsewhere who are on the front lines of a potential bio-terrorist attack.

"We are interested in not only overcoming an acute infection to save the individual, but at the same time helping to induce long-term immunity which will provide protection from a secondary infection," Karupiah said. The cytokine effect may apply not only to poxviruses, according to Karupiah, but to other generalized viral infections.

Previous studies have shown that poxviruses such as smallpox, monkeypox, and vaccinia, the virus used to vaccinate against smallpox, all make proteins that bind to IFN-g, to interfere with its signaling pathway. Karupiah's findings bolster suspicions that IFN-g, and other cytokines play key roles in pathogenesis of these infections. He and his colleagues are the first to rigorously characterize the distinct cytokine responses in susceptible mice and compare them to those observed in resistant mice.

Many in the field had believed IL-4 to be a hallmark for a type-2 cytokine response, and IFN-g, to be characteristic of the type-1 response. Karupiah's group demonstrated that simply taking away IL-4 in susceptible animals is not by itself enough to reverse susceptibility, "meaning that it's a lot more complicated than people think," said Karupiah. "But the prerequisite for efficient virus clearance seems to be high levels of gamma interferon production," he added.

The findings were published in the June 7 edition of the Proceedings of the National Academy of Sciences.