Flu epidemics cause up to half a million deaths worldwide each year, and emerging strains continually threaten to spread to humans and cause even deadlier pandemics. A study by McGill University professor Maziar Divangahi published by Cell Press on April 10 in the journal Immunity reveals that a drug that inhibits a molecule called prostaglandin E2 (PGE2) increases survival rates in mice infected with a lethal dose of the H1N1 flu virus. The findings pave the way for an urgently needed therapy that is highly effective against the flu virus and potentially other viral infections.
"Drugs that specifically target PGE2 pathways have already been developed and tested in animals, so our results have excellent potential for clinical translation, not only for the treatment of influenza, but other viral respiratory infections that interact with similar host immune pathways," says senior study author Divangahi, who is also a member of the Infectious and Immunity Axis at the Research Institute of the McGill University Health Centre (RI-MUHC).
Persistent threat to human health Despite the worldwide use of vaccination and other antiviral interventions, the flu virus remains a persistent threat to human health. To investigate molecular pathways that could be targeted by new interventions, Divangahi, an assistant professor in the Faculty of Medicine (Department of Microbiology and Immunology), and his team focussed on drugs such as aspirin and ibuprofen, commonly used to manage flu-like symptoms. By inhibiting a molecule called cyclooxygenase (COX), ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) lower the production of five major prostanoids -- immune molecules that contribute to pain and fever.
"But since these drugs inhibit all prostanoids, each may contribute differently towards the immunity against influenza virus," says Francois Coulombe, a McGill Ph.D. student and the study's first author. "Understanding their individual role is crucial in developing a new therapy."
Enhanced antiviral immunity Divangahi's research team found that mice genetically engineered to lack a member of the prostanoid family, PGE2, showed remarkably enhanced immunity to flu infection. Most importantly, the vast majority of these mice infected with a lethal dose of the H1N1 flu virus survived. Similarly, mice treated with a compound that inhibits PGE2 showed enhanced antiviral immunity and produced better survival rates following infection with a lethal dose of the flu virus compared with untreated mice.
"Previous studies produced conflicting results due to the inhibition of all prostanoids, not just PGE2," Divangahi says. "Our findings suggest that different prostaglandins have different roles in antiviral immunity and that specific inhibition of PGE2 will be an effective therapy against influenza viral infection by boosting immune responses."
- François Coulombe, Joanna Jaworska, Mark Verway, Fanny Tzelepis, Amir Massoud, Joshua Gillard, Gary Wong, Gary Kobinger, Zhou Xing, Christian Couture, Philippe Joubert, Jörg H. Fritz, William S. Powell, Maziar Divangahi. Targeted Prostaglandin E2 Inhibition Enhances Antiviral Immunity through Induction of Type I Interferon and Apoptosis in Macrophages. Immunity, 2014; DOI: 10.1016/j.immuni.2014.02.013
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