Spanish Flu in Monkeys Causes Uncontrolled Immune Response
By Michael Smith, Senior Staff Writer, MedPage Today
Published: January 17, 2007
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of
Medicine, University of California, San Francisco  Earn CME/CE credit
for reading medical news

http://www.medpagetoday.com/InfectiousDisease/URItheFlu/tb/4873

WINNIPEG, Manitoba, Jan. 17 -- The 1918-19 Spanish flu may have killed
50 million persons by unleashing an uncontrolled immune response that
fatally damaged lung tissue, researchers here say. Action Points
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Explain to interested patients that the 1918-19 Spanish flu pandemic
killed an estimated 50 million people, but it has not been clear why
that strain was so deadly.

Note that researchers have now been able to reconstruct the virus, in
special containment facilities, and test its effects in non-human
primates.

Explain that monkeys given the virus developed an uncontrolled immune
response that resulted in extreme damage to their lung tissue, which
may help explain the death toll in 1918-19.
The finding -- based on the first studies of the re-constituted virus
in non-human primates -- appears to parallel what happens when humans
are infected with the highly pathogenic avian flu now circulating in
birds, according to Darwyn Kobasa, Ph.D., of the Public Health Agency
in Canada.

"The H5N1 virus can also cause very serious disease and it appears to
do so in a way quite similar to the 1918 virus," Dr. Kobasa told
reporters.

He said studying the effects of 1918-19 virus -- painstakingly
synthesized from DNA sequence data in the agency's Level Four
containment facilities -- may help researchers predict the effects of
a new flu pandemic.

"A greater understanding of viruses that caused past pandemics will
help us predict what might be expected," Dr. Kobasa said.

With colleagues at the University of Washington in Seattle and the
University of Wisconsin in Madison, Dr. Kobasa compared the effects of
the 1918 virus with a modern circulating flu virus in a cohort of 10
macaques.

The central difference was that the innate immune response in the
seven animals infected with the 1918 virus was uncontrolled and did
not abate over time, Dr. Kobasa and colleagues reported in the Jan. 19
issue of Nature.

In contrast, the three animals infected with another H1N1 virus, the A/
Kawasaki/173/01 strain, had an initially robust immune response that
moderated as the virus was cleared, said Michael Katze, Ph.D., of the
University of Washington.

"Following that robust response, the monkeys quickly cleared the
virus," Dr. Katze told reporters.

The remaining seven animals continued to sicken, with an inflammatory
response that caused extensive damage to lung tissue, and they had to
be euthanized eight days after infection, he said.

The conclusion, he said, is that "instead of protecting individuals
that were infected with the highly pathogenic virus, the immune
response is actually contributing to the lethality of the virus."

Exactly why that should be so remains unclear, although suspicion
centers on a viral protein called nonstructural protein 1, or NS1,
which has been shown to modulate the immune response to the H5N1
virus.

The problem, Dr. Katze said, is that NS1 has been characterized as an
interferon antagonist, which would be expected to depress the immune
response, while in this case, the immune response was exaggerated.

The researchers said NS1 should be the target for future study to
clarify its role. One possible experiment, they said, would be to
synthesize a virus with most of the 1918 genes, substituting a modern
NS1 gene, and see what effect it has on animals.

"We know the 1918 virus grew tremendously well in non-human primates,
but we don't know why," said Yoshihiro Kawaoka, D.V.M., Ph.D., of the
University of Wisconsin. "That's what we need to study now."

The exaggerated immune response may also explain why the 1918-19
virus, unlike most flu strains, took its victims mainly from the young
and healthy -- those whose immune systems would respond most strongly,
the researchers said.

To ensure they were infected, the experimental animals were given
heavy doses of both viruses -- about seven million infectious units by
various routes -- but that is unlikely to explain the lethality of the
1918-19 virus, Dr. Kobasa said, because the other monkeys had a normal
response to the flu.

The test virus was created in the Canadian labs, using sequence data
reported beginning in 1999 by Jeffery Taubenberger, M.D., Ph.D., of
the Armed Forces Institute of Pathology in Rockville, Md., and
colleagues.

One possible clinical application of the research, Dr. Kobasa said, is
that first-responders to a new pandemic might be given antiviral
agents -- as is already proposed -- but might also be treated with
drugs to mute their inflammatory response.

The research is an important step in preparing for potential
pandemics, said Yueh-Ming Loo, Ph.D., and Michael Gale Jr., Ph.D., of
the University of Texas Southwestern Medical Center in Dallas.

"Unveiling the contribution of an aberrant host response to the
pathogenesis of the 1918 virus is just the beginning of efforts to
understand the disease mechanisms" of pandemic viruses, said Drs. Loo
and Gale, who were not involved in the research.

Writing in an accompanying News & Views article, they said a new
pandemic is a "real and continuing" threat that must be countered by
deeper understanding of the origin, transmission and virulence of
pandemic flu stains and how they interact with host immune systems to
cause disease.