Influenza: two promising new approaches.

Influenza is a disease that happens to individual patients, with results ranging from a few days of discomfort to, sometimes, serious illness or death--but it is also a public health problem that happens to communities. With the threat of pandemics and the continuing problem of evolving viral strains that can render vaccines ineffective from season to season, flu lends itself to the approaches and strategies of community health management.

So I was reminded when I read of two recently published studies--one produced by researchers in Australia, the other by scientists in the United Kingdom and the Netherlands. The first focuses on the role that "cytokine storms" play in the pathology of the flu and in flu pandemics; the other explores the mechanics of viral evolution.

Weathering the (cytokine) storm: a protein's key role A protein called SOCS4 has been shown to act as a brake on the immune system's runaway reaction to flu infection, providing a possible means of minimizing the impact of flu pandemics.

Scientists from Melbourne's Walter and Eliza Hall Institute have found that without SOCS4 the immune response to influenza infection is slowed and there is a vast increase in the number of damaging inflammatory molecules in the lungs. This flood of inflammatory molecules, known as a cytokine storm, is thought to contribute to flu-related deaths in humans.

Lukasz Kedzierski, PhD, Sandra Nicholson, PhD, and colleagues from the institute, with researchers from The University of Melbourne, made the discovery, which was published in the journal PLOS Pathogens.'

Suppressors of cytokine signaling (SOCS) molecules control the flow of chemical messages inside cells. Immune cells release cytokines to trigger an immune response that protects the body from infection. If too many cytokines are released, SOCS proteins suppress the activity of the cytokines to prevent unwanted inflammation and tissue damage.

According to Kedzierski, removing SOCS4 upset the normal immune response to influenza infection. "We showed that, following influenza infection, the immune system did not respond as quickly as expected and initially sent key immune cells to the wrong location in the body. In addition, inflammatory cytokines began to accumulate in the lungs, leading to a cytokine storm that causes significant damage to the tissue."

A cytokine storm can result in increased severity of symptoms and, in many instances, to multiple organ failure and death. "A cytokine storm is like an uncontrolled chain reaction, and the cytokines that normally stimulate the immune response continue to trigger other immune cells to produce more cytokines," says Kedzierski. "Our research suggests that SOCS4 keeps this response under control, preventing a cytokine storm in the lungs that can lead to a buildup of fluid that restricts breathing and can ultimately result in death."

Cytokine storms are believed to be the primary cause of death in young and otherwise healthy people who are infected with influenza, particularly pandemic flu strains. "Many of the estimated 50 million deaths caused by the 1918 flu epidemic are believed to have been caused by these cytokine storms," Kedzierski says.

Nicholson says the role of SOCS4 in the body was previously unknown. "When other SOCS proteins are removed from laboratory models, their function and the effect of their loss become immediately apparent. However, the SOCS4-deficient model appeared to be completely normal. It was only when we looked at the response to infection that we found the immune system was significantly affected by the loss of SOCS4.

"Knowing the target and function of SOCS4 may lead to us being able to control inflammation in severe cases of the flu or to the development of new, preventive therapies."

Caught in the act; how flu evolves to escape immunity Scientists have identified a potential way to improve future flu vaccines after discovering that seasonal flu typically escapes immunity from vaccines with as little as a single amino acid substitution. Additionally, they found these single amino acid changes occur at only seven places on the virus's surface. The research was published recently in the journal Science. (2)

"This work is a major step forward in our understanding of the evolution of flu viruses, and could possibly enable us to predict that evolution. If we can do that, then we can make flu vaccines that would be even more effective than the current vaccine," says Derek Smith, PhD, of the University of Cambridge, one of two leaders of the research.

The flu vaccine works by exposing the body to parts of inactivated flu from the three major different types of flu that infect humans, prompting the immune system to develop antibodies against these viruses. When exposed to the actual flu, these antibodies can eliminate the flu virus.

However, every two or three years the outer coat of seasonal flu, made up of amino acids, evolves, preventing antibodies that would recognize the older strains of flu from recognizing the new strain. As a result, the new strain of virus escapes the immunity that has been acquired as a result of earlier infections or vaccinations.

For this study, the researchers created viruses which had a variety of amino acid substitutions as well as different combinations of amino acid substitutions. They then tested these viruses to see which substitutions and combinations of substitutions caused new strains to develop.

They found that seasonal flu escapes immunity and develops into new strains typically by just a single amino acid substitution. Until now, it was widely believed that in order for seasonal flu to escape the immunity individuals acquire from previous infections or vaccinations, it would take at least four substitutions.

They also found that such single amino acid changes occurred at only seven places on its surface--all located near the receptor binding site, the area where the flu virus binds to and infects host cells. The location is significant because the virus would not change so close to the site unless it had to, as that area is important for the virus to conserve.

"The virus needs to conserve this, its binding site, as it uses this site to recognize the cells that it infects in our throats," says Bjorn Koel, a PhD candidate from Erasmus Medical Center in the Netherlands, and lead author of the paper.

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