Why The Flu Makes Some People Sicker
Than Others
Identifying key genes could help
identify those most at risk
FORT LAUDERDALE, Fla. (Nov. 3, 2006) _ With lessons
from the 1918 flu pandemic in the rearview mirror and the avian flu a
looming obstacle in the road ahead, researchers from Southern Illinois
University School of Medicine are trying to understand why a flu virus
kills some people but not others.
With the help of some high tech equipment,
well-defined mouse models and lots of analytical know how, physiologists
are beginning to hone in on the secret to this differential response.
It’s probably in the genes – and the proteins they encode.
Two studies to be presented at The American
Physiological Society conference “Physiological Genomics and
Proteomics of Lung Disease” have found that a strain of mice that is
more likely to die of influenza infection mounts a dramatically enhanced
immune response in the lungs compared to a strain of mice that generally
develops milder disease.
The long-term goal of these studies is to identify
genes that control the individual variation in inflammation during
influenza infection. This information could ultimately help identify
those most at risk to develop severe disease and die from the flu, and
help doctors direct vaccines, anti-viral and anti-inflammatory
medications to those who need them most.
The researchers will present the study
“Inflammatory responses in inbred mice with different susceptibility
phenotypes to Influenza A virus infection,” on Nov. 3. The study was
carried out by Rita Trammell and Linda Toth of the Southern Illinois
University School of Medicine, Springfield, Ill. The conference takes
place Nov. 2-5 in Fort Lauderdale
Lessons from 1918
“Flu epidemics typically kill the very old and the
very young. But the 1918 epidemic killed millions around the world,
including many healthy young adults. The healthy immune systems of young
adults produced an overly strong immune response that resulted in severe
inflammation of the lungs. Similar to the 1918 pandemic virus, most H5N1
avian influenza virus infections occur in young adults with no
pre-existing medical conditions,” Trammell noted.
“The recent emergence of the highly pathogenic H5N1
influenza virus has raised international concerns that continued
evolution of the virus could cause a pandemic with global health and
economic consequences,” Trammell said. “Should this occur, the ability
to identify those at highest risk for developing severe disease may help
to determine who would benefit most if vaccines and anti-viral
therapeutics are in limited supply,” she said.
“Studies to date have focused on the virus itself
to determine what makes some viruses killers,” she said. “Our research
looks at the role of the host’s genetic background, an area that has
remained largely unexplored.”
Flu fells some, not
others
Trammell and Toth infected two strains of
laboratory mice with an Influenza A virus. “Our previous studies
established that if you give the same dose of influenza A virus to both
strains of mice, about half of the BALB/cByJ (Type B) mice will die,
compared to about 10% of the C57BL/6J (Type C) mice,” Trammell said.
The researchers studied the early immune response
by examining the lung tissues of mice 30 hours after they were infected.
They measured the amount of virus, cytokines and myeloperoxidase that
was present in the lungs.
Cytokines and myeloperoxidase are proteins that
function in the immune response. Some cytokines are pro-inflammatory,
that is, they cause inflammation that helps to eliminate the pathogen.
In a well-orchestrated immune response, pro-inflammatory cytokines act
first and then recede once the virus is eliminated. Anti-inflammatory
cytokines regulate the immune response to minimize damage to normal
tissues. Myeloperoxidase is an enzyme that indicates the number of
neutrophils -- a type of white blood cell -- present in the lung.
Inflammation of lungs
is the difference
The researchers found the level of virus in the
lungs of the two mouse strains did not differ significantly. However,
all the pro-inflammatory cytokines, with one exception, were
significantly higher in the Type B (disease susceptible) mice when
compared to Type C (disease resistant) mice.
“Although viral titers are equivalent, B mice
develop a much greater pro-inflammatory response during influenza
infection than C mice, which may contribute to the differential
mortality in these strains,” the authors concluded.
A related study, “Microarray analysis of gene
expression in the lungs of influenza-infected C57BL/6J and BALB/cByJ
mice,” complemented these findings. In this study, Toth and fellow
Southern Illinois University School of Medicine researcher, Ming Ding,
examined what happened to immune-related messenger RNA (mRNA) levels
after the two mouse strains were exposed to the flu. The immune-related
mRNAs evaluated in this study ultimately produce the proteins important
to the immune response.
Like the other study, these researchers found no
difference in the amount of virus in the lungs of the two mouse strains
after influenza infection. But they were “amazed at the difference in
immune-related mRNA levels between the two strains,” Trammell said. When
compared to uninfected control mice, the mRNA levels in Type B mice were
on average 24 times higher, with some types of mRNA increasing more than
100 fold. In contrast, mRNA levels in Type C mice only increased less
than 3-fold after infection.
“Both studies show clear and dramatic differences
in the pulmonary inflammatory response of the Type B strain of mice, as
compared with Type C strain, after infection with the same dose of
influenza virus,” Trammell said. “These distinctive responses to the
identical virus challenge suggest that the genetic control of the
inflammatory response differs between these two strains.”
Toth and Ming will present their study at the
conference on Nov 3.
“Our long-term goal is to identify genomic regions,
genes, and alleles that control variation in inflammation during
infection with influenza virus,” Trammell said. “The identification of
these genomic regions has enormous implications for understanding and
avoiding the fatality associated with infection.”
These studies are at the cutting edge of proteomic
and genomic research, which has taken a big leap with recent advances in
imaging technology and new methods of analyzing masses of data.
Funding
The research was funded by the National Institutes
of Health.
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The
American Physiological Society was founded in 1887 to foster basic and
applied bioscience. The Bethesda, Maryland-based society has 10,500
members and publishes 14 peer-reviewed journals containing almost 4,000
articles annually.
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