June 07, 2004
Clue to Smallpox Immunity
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. The discovery could pave the way to better protection for
humans against the threat of smallpox, a related virus, as a weapon of
bioterrorism.
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 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.
“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.”
Gunasegaran 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 tumor 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. The findings were
published online in the June 7 edition of the Proceedings of the
National Academy of Sciences.
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
bioterrorist 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.”
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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