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. © Kerem Yucel - stock.xchng, Kerem Yucel - stock.xchng

Influenza Virus: A New Therapeutic Strategy

Dr Béatrice Riteau (Université Claude Bernard Lyon 1/INRA) and her team from the research unit VirPath headed by Pr Bruno Lina have discovered a molecule that counteracts the deleterious effects of the immune response and inflammation in the lung when infected with influenza virus. This molecule targets a host molecule, instead of the virus, which helps the body to defend itself efficiently avoiding the emergence of resistant viruses to the current antiviral drugs. This discovery, published on 3 December 2012 in the Journal of Clinical Investigation, could favor the development of efficient treatments against multiple strains of flu (such as highly pathogenic H5N1 and pandemic H1N1), regardless of their virulence or epidemic power.

Updated on 03/06/2013
Published on 12/03/2012

Influenza is a contagious disease which is responsible for seasonal epidemics or sporadic pandemics in humans or animals: It is a major public health issue worldwide. Beyond the sanitary cost relative to flu epidemics (several billions of dollars worldwide every year), the emergence of strains resistant to antiviral treatments is a real challenge for research. Treatments currently on the market solely target viral proteins, allowing them to mutate.

Electron microscopy view of the Influenza virus A/PR/8/34 (H1N1). © ©UCBL, Fatma Berri/Cecil
Electron microscopy view of the Influenza virus A/PR/8/34 (H1N1) © ©UCBL, Fatma Berri/Cecil
In order to bypass this problem, researchers of the Université de Lyon 1 and INRA, in collaboration with international research teams, developed a strategy that targets the host cells rather than the virus. Among all types of flu viruses, type A (IAV) are among the most frequent and virulent, also responsible for seasonal epidemics. Though, the infection mechanism of IAV is not well understood. It involves both viral and immune traits. Both innate and adaptive components of the immune system are activated shortly after the viral infection, which insures an efficient defense line against IAV. However, excessive inflammation, particularly in the lower respiratory tract, may result in alveolar damage limiting respiratory capacity and deteriorate the clinical outcome of IAV infections.

Scientists found that a protein called PAR1 is responsible for a cascade of events leading to the inflammation in mice that were infected by IAV. When this protein is deficient, animals prove to be more resistant to IAV infection. Scientists then administered an antagonist molecule of this protein to infected mice and observed a greater survival rate, when they shouldn’t have lived through. This molecule thus controls the impact of the virus on lung inflammation. Finally, this antagonist operates even when it is given 48 to 72 hours after virus inoculation.

More remarkably, they have shown that by targeting the host cells, this strategy is also very efficient in a strain-independent manner. Indeed, it has proven its efficiency, in animals, upon infection with H1N1, H3N2 subtype viruses (those circulating during seasonal flu), highly pathogenic H5N1 viruses and H1N1 2009 pandemic virus that have developed resistance to oseltamivir (Tamiflu). This study confirms that the development of an alternative treatment to current antivirals minimizing the emergence of resistant viruses is possible.

Antagonist molecules of PAR1 are currently under phase 3 clinical trials for their potential action against thrombosis. Considering that we know the effects of this molecule, notably side effects, the development of a new treatment against the flu should be all the more rapid. A strategy favoring a targeted action on the immune response instead of the virus itself represents an unprecedented way in the fight against viruses resistant to current treatments.

Contact(s)
Scientific contact(s):

Press Relations:
INRA News Office (33 (0)1 42 75 91 86)

Reference

Khaled Khoufache*, Fatma Berri*, Wolfgang Nacken, Annette B. Vogel, Marie Delenne, Eric Camerer, Shaun R. Coughlin, Peter Carmeliet, Bruno Lina, Guus F. Rimmelzwaan, Oliver Planz, Stephan Ludwig, and Béatrice Riteau. PAR1 contributes to influenza A virus pathogenicity in miceThe Journal of Clinical Investigation, 3 December 2012. doi:10.1172/JCI61667 
*First co-authors