Dangers of 'bird flu'


1. On the verge of disaster?

2. Mixing and matching genes

3. Responding to infection

4. Science fights flu

Influenza vaccines can take six months to produce, and the process must be repeated each year. How fast could vaccine-makers respond to an outbreak of H5N1? Photo: CDC.

Understanding how a cell responds to influenza may help us help the body fight the disease.

Avian influenza could brew in big chicken farms, like this one in Florida. Some experts say all poultry should be vaccinated against avian influenza; others think that would only accelerate the evolution of even tougher strains of virus or make healthy chickens look sick on antibody tests. Photo by Larry Rana, USDA.

A U.S. Army influenza ward in Luxembourg, during the 1918 epidemic. Photo courtesy National Museum of Health and Medicine, Armed Forces Institute of Pathology, Washington, D.C.

Vacuuming up vaccine
Aside from going to Mars, vaccines are the best way to avoid flu.

So if H5N1 is scourging Asian poultry and threatening to kill large numbers of people, why not just cook up a vaccine?

Vial of influenza vaccine.First, consider the time problem. Using conventional techniques, experts say it takes six months to make a vaccine. If a bird flu does figure out how to jump between people, six months might translate into "never" for the millions of victims who could die in the meantime.

Second, this avian flu is deadly to fertilized chicken eggs, which are used to grow viruses to make vaccine. To sidestep these problems, some experts have begun to use "reverse genetics." That means deliberately assembling vaccine viruses while omitting the component that kills chicken eggs.

Robert Webster and colleagues at St. Jude Children's Research Hospital in Tennessee have used reverse genetics to make vaccine stock for H5N1, but the stuff has not been tested for effectiveness or safety. Bonnie Cameron, who handles press relations at St. Jude, says the hospital is only at the start of the vaccine pipeline. "We will manufacture the seed stock here, and then it will get turned over to the CDC, which would be in charge of making it available for clinical trials."

She says the St. Jude crew made a seed stock last year against the 1997 version of H5N1, but the CDC and WHO did not proceed with clinical trials.

Understanding a killer
While the vaccine machine cranks up, the tools of cell biology are improving our picture of what happens when influenza attacks a cell in the human respiratory tract -- its usual target. Stacey Schultz-Cherry, an assistant professor of medical microbiology and immunology at University of Wisconsin-Madison, wants to know what happens when a lung cell is infected. "Does it die?" she asks. "What signaling pathway is activated, what antiviral pathways are activated?"

Flu causes cells in the upper respiratory tissue to commit suicide, Schultz-Cherry says, through programmed cell death, or apoptosis. But that could be good or bad for the flu victim, she points out. Viruses can only grow in an intact cell, but then they need a damaged cell membrane to exit the cell. Thus cell death could cut both ways, she stresses. "It allows virus to escape, but it may reduce overall viral infection if less virus is made."

Hordes of chicken inside coop.

Animals use apoptosis to get rid of unwanted cells, both as an embryo and in adult life. The P53 cell-death pathway, for example, often kills cancer cells. If it becomes inactive, fast-growing cancer cells can escape destruction and multiply.

P53 may also play a part in reducing viral infections, since when Schultz-Cherry's lab interfered with the P53 pathway, about 10,000 times as much virus appeared in the cell culture. The conclusion, Schultz-Cherry says, is that "Death through apoptosis looks good for cells and the organism." She has sent those results to a scientific publication.

If future tests confirm her results, enhancing the P53 pathway may help flu victims kill their virus-infected cells and reduce the amount of virus in the body. Similarly, helping chicken embryos control virus could also simplify the production of vaccines against viruses like H5N1 that normally kill bird embryos.

In a second line of research, Schultz-Cherry located a compound, called TGF beta (transforming growth factor beta), that stimulates the human immune system during flu infections (see "Influenza Virus Neuraminidase ..." in the bibliography). When she disabled the TGF beta response in a culture of human cells and in test animals, flu viruses that were once tolerable became lethal. It's an intriguing result, but Schultz-Cherry is not sure what it means. Is TGF part of the P53 regulatory pathway? Would increased levels of TGF-beta help protect cells against flu?

Sick, masked patients look up from hospital cots.

What to do?
Even before important questions like these are answered, science has suggestions for battling the next pandemic. Webster, of St. Jude, suggests these four steps (see "Are We Ready ..." in the bibliography):

Stockpile enough antiviral drugs to limit the symptoms and spread of influenza.

Make and test a vaccine to match the emerging pandemic strain.

Solve the liability and intellectual-property snafus that bedevil the prospects for making vaccine with reverse-genetics.

Ramp up the global capacity to manufacture flu vaccine.

In comparison to, say, going to Mars or reducing the level of incarceration in America, these tasks might not seem terribly difficult. The big question, according to those few who fret about flu, is whether anyone will listen before it's too late.

Nothing but ears in the flu bibliography.

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