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In Search of the Spanish Flu's Smoking Gun

The influenza pandemic of 1918, aka the Spanish Flu, remains the most deadly in recent history, with death estimates ranging between 20 million and 40 million people worldwide. According to some experts, influenza may have killed roughly 40 percent of U.S. soldiers during World War I.

Now, a cross-country team of eminent researchers led by Adolfo García-Sastre, Ph.D., professor of microbiology at Mount Sinai School of Medicine, New York City, has set out to answer why. The team is investigating what in the 1918 virus’ genetic, structural, and molecular make-up could have wreaked such havoc in humans. The answer could help provide a blueprint for developing antiviral agents and vaccines to arrest and disable similarly dangerous flu strains.

The key to solving this long-unanswered puzzle, says Dr. García-Sastre, is through coordination, collaboration, and old-fashioned conversation between people of diverse interests and expertise. Even before NIAID funded the project in July 2004, the team had begun meeting twice a year for the past two years, as well as interacting day-to-day through conference telephone calls and email.

"Our main goal is to try to understand the signatures of virulence," says Dr. García-Sastre. "We want to know more about why some strains bring about a more severe molecular response in a host."

To tackle this question, the team is partially piecing together the 1918 strain, beginning with human tissue preserved during that time period. They are then dissecting the 1918 genes and exploring how the proteins they encode function and interact. Because host response is also of utmost interest, they are studying the effects of the 1918 genes in mice, ferrets, and nonhuman primates.

In one recent study, when human 1918 HA and NA genes were added to a lethal mouse influenza virus strain, the strain remained highly lethal to mice. (Generally, human influenza virus strains do not cause disease in mice.) Lung tissue of the mice revealed that, in mice infected with the strain containing 1918 HA and NA genes, the lungs were heavily damaged, and many genes associated with the inflammatory response were activated. In mice infected with a control strain containing HA and NA genes from a 1999 human influenza virus, the mice survived, their lungs were not damaged, and their inflammatory genes were not activated. This finding highly suggests that the glycoproteins of the 1918 virus contributed to its increased pathogenicity and leads researchers to ask if host genes can contribute to its virulence, or if they are merely responding to that virulence.

Photo of Adolfo Garcia-Sastre and team
Adolfo Garcia-Sastre (first row, far right) has assembled a top-notch team for studying the 1918 flu virus.

In addition to Mount Sinai, team members represent the Armed Forces Institute of Pathology, Washington, D.C.; Scripps Research Institute, LaJolla, CA; Centers of Disease Control and Prevention, Atlanta; United States Department of Agriculture, Athens, Georgia; and University of Washington, Seattle.

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Last Updated October 13, 2010