Environmental Factor, September 2009, National Institute of Environmental Health Sciences
Research Suggests Viral Protein Manipulates Host Cells to Cause Flu-like Symptoms
By Brian Chorley
In response to the current H1N1 pandemic, the scientific community has increased its efforts to better understand how influenza virus spreads and how to mediate its adverse health effects. Physiologist Sadis Matalon, Ph.D., of the University of Alabama in Birmingham (UAB), and an NIEHS-supported research group, which included influenza experts Diana Noah, Ph.D., and James Noah, Ph.D., of the Southern Research Institute Emerging Infectious Diseases section in Birmingham, are currently exploring such issues by determining the mechanisms by which influenza virus invades its host and propagates.
In their recent study (http://www.ncbi.nlm.nih.gov/pubmed/19596899?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) , available online from the Journal of the Federation of American Societies for Experimental Biology (FASEB), Matalon (http://www.sadismatalon.com/) and his research team demonstrated for the first time how a specific viral protein, M2, decreases airway cell ion channel activity, which can lead to flu symptoms such as pulmonary edema. Understanding this mechanism may lead to "new therapeutic strategies for altering the progression of the viral infection" and for maintaining alveolar fluid absorption, the authors conclude.
According to the researchers, influenza is a highly contagious respiratory virus responsible for an estimated 36,000 deaths annually in the U.S. alone. It infects humans and other animal species, such as dogs, horses, pigs and birds. The virus is highly adaptable to its environment because of its ability to incorporate genetic material from different viral strains, thereby creating a novel strain not recognized by the immune system of the host. For example, the current H1N1 strain evolved from strains that previously infected humans, birds and swine.
Understanding the mechanisms by which influenza viruses evolve, invade and replicate also clues scientists as to why viruses create flu-associated symptoms. Many of the respiratory symptoms can be attributed to signaling changes mediated by the airway epithelial cells. The virus first encounters this cellular lining, which protects the airway from environmental challenges. These cells were the focus of Matalon's study.
Specifically, changes in sodium transport across the epithelial cell lining after influenza virus exposure was measured. Sodium transport directly influences the absorption of fluid that lines the trachea and distal airways. Abnormal buildup of this fluid, or pulmonary edema, reduces the ability of oxygen exchange in the lung, which can be fatal. In the study, the researchers demonstrated that the M2 protein attenuates the presence of the epithelial sodium transport channel ENaC.
M2 protein itself is an ion (proton) channel and is utilized by the virus to create an environment conducive for replication. Since M2 protein functions in the same cellular space as ENaC, the research team looked for interaction between the two ion channel proteins that could explain M2-mediated regulation of ENaC. Surprisingly, they found that M2 increased targeted degradation of ENaC through an indirect mechanism involving reactive oxygen species production and a downstream protein kinase cascade.
Decreased amounts of active ENaC through the action of viral M2 protein may contribute to fluid buildup in the airway. This buildup could lead to pulmonary edema, as well as contribute to less serious flu symptoms, such as runny nose. Medications that specifically target the viral M2 protein, such as amantadine, should act to dampen these symptoms by inhibiting ENaC depletion.
Unfortunately, due to their highly adaptable nature, many viral strains are amantadine-resistant, limiting the effectiveness of this medication as an anti-viral treatment. Evidence provided by this study demonstrates, however, that targeting M2 protein may have multiple beneficial effects. Perhaps findings such as these will lead to future efforts to develop novel drug therapy that targets the viral M2 channel.
The study was supported by grants from multiple institutes of the National Institutes of Health, including the National Institute of Environmental Health Sciences. The findings will be published in the November 2009 edition of FASEB.
Citation: Lazrak A, Iles KE, Liu G, Noah DL, Noah JW, Matalon S. (http://www.ncbi.nlm.nih.gov/pubmed/19596899?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) 2009. Influenza virus M2 protein inhibits epithelial sodium channels by increasing reactive oxygen species. FASEB J. [Epub ahead of print]
(Brian Chorley, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Environmental Genomics Group.)