H1N1 Influenza Virus Used New Biochemical Trick to Cause Pandemic

H1N1 Influenza Virus Used New Biochemical Trick to Cause Pandemic
Washington-based Structural Genomics Collaboration Plays Key Role in Discovery
SEATTLE, WA,  Aug. 5, 2010 - Today, scientists announced the discovery of genetic changes that affect the spread of Influenza virus from one host to another. In a report in the current (Aug. 5, 2010) edition of Public Library of Science (PLoS) Pathogens, an international team of scientists - including members of the Seattle Structural Genomics Center for Infectious Disease (SSGCID) - sheds new light on the Influenza virus, showing that the recent pandemic-causing H1N1 flu virus used a new biochemical trick to spread efficiently in humans.
Led by Peter Myler, Ph.D., of Seattle Biomedical Research Institute (Seattle BioMed), the SSGCID brings together a consortium of Washington State-based organizations to provide a "blueprint" for the development of new drugs, vaccines and diagnostics for deadly infectious diseases, like the flu. Funded by a $30.6 million contract from the National Institute of Allergy and Infectious Diseases (NIAID), which is part of the National Institutes of Health (NIH), the Center uses state-of-the-art high-throughput technology to experimentally determine the three-dimensional structures of proteins from a number of bacterial, viral, fungal and protozoan pathogens. In addition to Seattle BioMed, the SSGCID members include Emerald BioStructures, the University of Washington and the Pacific Northwest National Laboratory (Battelle Memorial Institute).
Influenzavirus A, scientists well know, is a crafty pathogen constantly changing to evade host immune systems and jump from one species, like birds, to another, such as mammals. The H1N1 flu virus caused a worldwide epidemic in 2009 and 2010, sickening as many as 34 million Americans and causing up to an estimated 6,000 deaths in the United States.
The new work expands the repertoire of known factors flu viruses can use to hijack a host cell and amplify infection in mammals, including humans. The discovery not only yields new insight into the subtle biology of flu, but also reveals another genetic marker public health officials can use to predict pandemics.
According to Yoshihiro Kawaoka, Professor of Pathobiological Sciences at the University of Wisconsin-Madison's School of Veterinary Medicine and senior author and leader of the biological aspects of the new work, the H1N1 virus is really a combination of four different avian and swine flu viruses that have emerged over the past 90 years. It even includes genetic residue of the 1918 pandemic virus, an influenza that killed as many as 20 million people.
Typically, the presence of two amino acids -- lysine and asparagine -- in specific sites on the viral polymerase protein, a protein responsible for replicating the genetic material of the virus, are required for a bird flu virus to make the jump from its avian host to replicate efficiently in human cells. However, the swine flu H1N1 virus lacked both of these amino acid building blocks, posing a puzzle for scientists.
The new study found that changes in amino acid resides (mutations) located on the surface of the "PB2" polymerase protein are responsible for the H1N1 virus' ability to adapt to and co-opt human cells. "This pandemic H1N1 virus has different mutations and that is why it can replicate so well in humans," says Kawaoka, who also is a professor at the University of Tokyo. "This gives us another important genetic marker to help predict the possibility of future flu pandemics."
The new PLoS Pathogens report also includes X-ray crystallographic data for the three-dimensional structure of the H1N1 protein, which carries the key lysine reside that originated from an avian virus. The exquisite X-ray crystallographic study performed by SSGCID compared the structure of the swine H1N1 PB2 to that of the bird H5N1 PB2.
According to Bart L. Staker of Emerald BioStructures, a crystallographer on the SSCGID team, "the structural data reveals changes in the surface shape of the avian virus PB2 protein compared to that of the swine H1N1 PB2, which could, in turn, be responsible for thwarting factors in the human cell that would otherwise inhibit virus replication."
The structural data, says Kawaoka, provides essential insight into how the virus may interact with the host cell or other virus components in infected cells, and could help provide a basis for antiviral agents that could be used to thwart a future flu virus that uses the same amino acid trick to infect human cells. "Clearly, the host factors in human cells are doing something. The structure may help us better understand the interplay between the virus and the host human cell."
Lance J. Stewart, CEO of Emerald BioStructures noted that "this international collaborative research on influenza virus demonstrates that the rapid spread of the 2009 H1N1 swine flu virus is likely the result of a constellation of genetic changes that alter three dimensional shape of the surface of one part of the viral polymerase.  Thankfully, even though the swine flu H1N1 can replicate efficiently in the human population, it was not nearly as deadly as the 1918 virus. We still have much to learn about the ongoing battle between human host and virus pathogen." 
Myler said he's proud the SSGCID has played a role in shedding new light on the H1N1 virus. "By determining the three-dimensional structure of this protein, we have new information that can be used to develop much-needed new interventions for this deadly disease," explained Myler.
Seattle BioMed is the largest independent, non-profit organization in the US focused solely on infectious disease research. Our research is the foundation for new drugs, vaccines and diagnostics that benefit those who need our help most: the 14 million who will otherwise die each year from infectious diseases, including malaria, HIV/AIDS and tuberculosis. Founded in 1976, Seattle BioMed has nearly 350 staff members. By partnering with key collaborators around the globe, we strive to make discoveries that will save lives sooner. For more information, visit www.seattlebiomed.org.
Emerald BioStructures is an integrated gene-to-structure contract research organization that provides collaborative drug discovery services to pharmaceutical companies, biotechnology companies, academic institutions, and government agencies. The company operates a high-throughput platform leveraged for fragment-based lead discovery and structure-based drug design. Emerald's work provides a solid foundation for the discovery of highly selective, efficacious drugs and vaccines.  www.emeraldbiostructures.com.
The Seattle Structural Genomics Center for Infectious Disease (SSGCID) is a consortium of four Pacific Northwest institutions (Seattle Biomed, Emerald BioStructures, the University of Washington and Pacific Northwest National Laboratory) funded by the National Institute of Allergy and Infectious Diseases (NIAID),  (contract number HHSN272200700057C) to apply genome-scale approaches in solving protein structures from biodefense organisms, as well as those causing emerging and re-emerging disease.