Scientists know relatively little about the immune response to smallpox, primarily because the virus has been all but eradicated for years. Researchers and public health officials therefore had little motivation to understand the immune responses generated. Also, although Karupiah's group has been working with mousepox for 15 years, investigators worldwide have been generally wary of working with the pathogen for fear it might spread to other mouse colonies. Smallpox was one of the biggest human scourges, said Karupiah, noting that in some populations there was a 30% mortality rate. And yet, because it was successfully eradicated, no one was interested in understanding how individuals recovered. But now, of course, the interest is back because of the threat of bioterrorism.

Karupiah's group used immunohistochemistry to look for cytokine proteins in vivo, an approach that insures the detected cytokines actually are being produced by the host during the course of infection. They found that while the messenger RNA for most of the cytokines is expressed following infection, the protein is not always produced ”an important observation, since the cytokine only has a biological effect when the protein is produced. Investigators, therefore, have been misled at times by looking only at gene expression.

Interestingly, the pattern of protein production also differs between organs. Unexpectedly, in animals that made IFN-g, investigators found the protein in the spleen and not the lymph node, though both organs are associated with the generation of an immune response. Conversely, they found IL-2 in the lymph node but not in the spleen. The reasons why this happens are still unclear, said Karupiah, but understanding them may help researchers figure out what constitutes an effective immune response.

The mousepox model has proven a useful tool for studying smallpox biology because of the ample mouse gene knockouts available. Karupiah also emphasizes the importance of the mousepox virus having co-evolved with the mouse much as smallpox has co-evolved with humans. For millions of years, the mouse immune system has adapted to the pathogen, and the pathogen has likewise adapted to new adaptive responses generated by the host. Scientists do not have the opportunity to study the outcome of such a longstanding immunological arms race in a mouse model of, for example, influenza.

Karupiah and colleagues continue to probe the mousepox-triggered immune response. They're investigating not only interferon response, but also the killer T cell and antibody responses.

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