The influenza virus’ ability to mutate quickly has produced new,
emerging strains that make drug discovery more critical than ever. For
the first time, researchers at Seattle BioMed, along with collaborators
at the University of California, San Diego School of Medicine, St. Jude
Children’s Research Hospital and the University of Washington, have
mapped how critical molecules regulate both the induction and resolution
of inflammation during flu infection. The results are published this
month in the journal Cell.
Flu is an elusive foe
The
influenza virus mutates extremely quickly, with different strains
causing seasonal epidemics each year. Genetic shuffling between
different viruses can increase influenza’s ability to spread, causing
devastating epidemics and pandemics. The 1918 flu pandemic, the first to
involve the H1N1 strain, cost the lives of 50 to 100 million people,
and even a typical flu season can cost as many as 50,000 lives a year.
Vaccines
are a highly effective way to combat the flu, but because manufacturing
and distributing vaccines takes such a long time, it is impossible for
public health officials to wait until they know for certain which strain
of flu will prevail in a given season. “Because of this, drugs are
critically important to combat flu infections,” says Alan Aderem, Ph.D.,
principal investigator on the research. “But at the moment, we have
very few drugs at our disposal, and resistance is already beginning to
appear against our limited arsenal.”
Systems biology yielding new insights
The
solution for Aderem and scientist Vincent Tam, Ph.D., was to take a
systems approach to better understand the interactions between the flu
virus and the human host. They teamed up with Oswald Quehenberger,
Ph.D., and Edward Dennis, Ph.D., of the University of California, San
Diego School of Medicine to tackle this problem. Systems biology uses
computational tools to integrate the study of genes, proteins and
lipids. This comprehensive approach unravels the complexities and
provides a holistic view of the host-pathogen interaction. This
strategy, focusing on lipid components, had never before been applied to
the flu infection.
There is a class of lipid mediators that act
as signaling molecules to control inflammation, and have long been known
to play a role in stimulating an inflammatory response. “But some of
these regulatory lipids, including ones derived from the omega-3 fatty
acids and known as DHA and EPA, are also involved in resolving
inflammation and bringing the body back to homeostasis,” observed
Quehenberger and Dennis. This dual role makes lipid mediators a critical
player in the interaction between the virus and the human immune
system.
The research team studied 141 different lipid metabolites
and incorporated them into networks comprising lipids, genes and
proteins of host responses to two different strains of the flu virus,
one mild and one severe. In doing so, they found that infection by the
mild H3N2 strain induced a pro-inflammatory response followed by a
distinct anti-inflammatory response. This represented a case of a
clearly regulated inflammatory response. In contrast, infection by the
severe H1N1 strain resulted in overlapping pro- and anti-inflammatory
states, indicating that the virus had disturbed the normal methods of
controlling inflammation.
Importantly, the study discovered that
many of the results found in the mouse model were recapitulated in
humans by studying nasal wash samples collected from flu-infected
patients. “It is absolutely crucial to confirm the relevance of these
molecules in humans if we want to look for effective therapeutics
against flu,” says Aderem.
Moving to new interventions
“Once an infection starts, it’s too late for vaccines,” says Dennis, explaining the urgent need for drugs to combat the influenza virus. Emerging strains like H5N1 and H7N9—more commonly known as bird flu—are especially dangerous, killing about 60% of the people they infect, according to data from the Centers for Disease Control and Prevention. Because drugs fight infections that are already underway, they are a critical player in keeping the multitude of flu strains under control.
A
more complete understanding of how the flu virus interacts with the
human immune system, including the role of lipid mediators, could reveal
important new drug targets. “If we can perturb the balance between pro-
and anti-inflammatory responses in flu patients, we can help them
regulate their immune systems to control their infections,” says Tam.
Source: Seattle Biomedical Research Institute
