Why are viruses able to infect some species and not others? And - a question that has been on a number of people's minds with respect to influenza virus - how does a virus jump species?

One short answer: several ways. Another: We don't really know.

"We are mostly ignorant about how [species jumping] happens, because it is quite rare. But when it does happen, it can be pretty catastrophic," Grant McFadden, co-director of the BioTherapeutics Research Group at the Robarts Research Institute in London, Ontario, told BioWorld Today. He cited severe acute respiratory syndrome as an example of what happens when viruses do suddenly jump species.

There are two known mechanisms that determine whether a virus will be able to infect a given species, or whether it will be rebuffed.

"One camp needs specific receptors - many viruses fall into that camp," McFadden said. The type of receptors a virus uses, and how common it is, determines both host range and the cell types infected. Rabies virus, for example, which uses evolutionarily conserved acetylcholine receptors, infects neuronal cells in a wide range of species. In virological terms, it is promiscuous.

Influenza is another virus with the ability to switch species, making it of concern, to say the least. The influenza virus enters cells through the binding of viral hemagglutinin to host-cell receptor surface molecules called glycoproteins and glycolipids.

Because glycoproteins and glycolipids vary more across species than acetylcholine receptors, a given influenza strain is more restricted in its host range. However, the influenza virus has another mechanism to expand the host range of a given strain. The influenza virus has a segmented genome, meaning that when two different influenza strains are replicating in the same host, those segments will re-assort independently. Since both human and bird strains are able to infect pigs, the typical way in which an avian flu jumps to man is through mixing segments with a human virus in pigs.

In the case of H5N1, what is known about the general mechanisms of influenza virus replication does not fully explain its host range. The avian virus appears to be able to infect humans directly, without attending genetic mixers in pigs first. Possible human-to-human transmission of H5N1 also has been reported by the World Health Organization. In the Oct. 8, 2004, issue of Science, researchers published evidence that H5N1 is able to infect cats, which normally are immune to influenza. Transmission occurred when the cats ate infected birds and via cat-to-cat transmission. Since 1997, when H5N1 first caught the attention of the medical community, the virus also has become much more efficient at duck-to-duck transmission. (It also has become more virulent in ducks, but virulence is determined by different mechanisms.)

Not everyone believes that this is the harbinger of an H5N1 pandemic. Peter Palese, chair of the department of microbiology at New York's Mount Sinai School of Medicine, pointed out that both in cases of direct bird-to-human transmission and in the cat data reported in Science, exposure to high levels of the virus was necessary for infection to occur.

That does not mean Palese discounts the likelihood of a flu pandemic, but just that an overly strong focus on H5N1 to the detriment of other strains might be misguided. "What is warranted [and] where there is little or no disagreement among scientists, is a continued surveillance of influenza viruses, not only in humans but also in different animal species and commercial operations. Furthermore, the stockpiling of antiviral drugs and the development of new vaccines is highly recommended to be better prepared for a potential pandemic outbreak," he wrote in a review article in the December 2004 issue of Nature Medicine.

Act 2: Manipulating Signal Transduction

Other viral host ranges do not depend on receptors; instead, they manipulate signal transduction pathways within the cell. One of those viruses is myxoma virus, a type of pox virus McFadden and his group study. In the December 2004 edition of Nature Immunology, they report, along with colleagues from Washington University in St. Louis, on the mechanism that restricts myxoma's host range.

Myxoma is anything but promiscuous; in fact, its host range is so highly restricted - it infects only rabbits - that it was used as the basis of a rabbit extermination program in Australia in the 1950s. The virus was introduced into wild rabbit populations, which had become a major plague. Using the virus was possible only because of its complete specificity to infecting rabbits.

"If you infect any other animal, the virus vanishes. In fact, the three lead [principal investigators] injected themselves with live virus" to convince Australian regulatory authorities to go ahead with the extermination program, McFadden said.

"We initially got into this not to study tropism or signaling. We started by looking for receptors" responsible for myxoma's specificity to rabbits, McFadden said. "But try as we might, we could never find any receptors. Instead, we found differences in signal transduction."

What McFadden and his colleagues found is that the virus inhibits the interferon response in infected rabbits. When myxoma virus infects rabbit cells, it inhibits the Erk kinase. Erk kinase usually activates interferon-regulating factor, which in turn activates interferon responses. When myxoma infects anything other than rabbits, it is unable to inhibit Erk kinase, and is promptly dispatched by the host interferon response.

His findings have taken McFadden in an unexpected direction: Because myxoma virus will infect those cells, and only those cells, with a disabled interferon response, it now is being tested for its ability to treat cancer cells. The virus is being tested by the Oncolytic Virus Consortium, and McFadden said that Gaithersburg, Md.-based Wellstat Therapeutics has expressed a possible interest in its development.

And the Australian rabbits? Well, it worked in one sense - the myxoma virus did not break the species barrier when introduced in the wild. But a few rabbits naturally were resistant to myxoma virus, and since rabbits are more promiscuous than the myxoma virus itself, it was a basic Darwinist homily. The resistant survivors bred, and now, some generations later, most of the rabbit population of Australia is highly resistant to myxoma virus.