Despite vaccination and currently available antiviral drugs, influenza infections are still making a huge impact on human health worldwide. In Germany alone, influenza infections cause several thousand deaths each year. Patients with weakened immune systems are particularly vulnerable to the virus’s fatal consequences. New strains of the influenza virus, for example the H1N1 virus (“swine flu”) which spread throughout the world in a matter of weeks in 2009, carry additional risks. Up to now the only weapons available for the prevention and treatment of influenza infection were vaccines and antiviral drugs which target the virus itself. Due to the viruses’ extreme adaptability, vaccines must be constantly tailored to the virus strain currently in circulation. In addition, standard antiviral drugs are proving increasingly ineffective as a growing number of viral strains are developing resistance to them. Scientists at the Max Planck Institute for Infection Biology in Berlin have now succeeded in identifying targets that could be less susceptible to the development of resistance. (Nature, online publication on January 17th, 2010)
Figure Using a genome-wide RNA interference screening approach, scientists reveal human host factors crucial for replication of different influenza A viruses, including the pandemic swine-origin H1N1 virus. The image shows a scanning electron micrograph of the pandemic influenza strain (A/Hamburg/04/09) emerging from human lung cells (A549) 18 hours after infection.
Image: Max Planck Institute for Infection Biology / Volker Brinkmann
Influenza viruses require several hundred human proteins to replicate
Influenza viruses are highly dependent on proteins of their infected cells for reproduction; however, the identity of many of these proteins has remained enigmatic. Scientists working in this research field have made use of a new technology known as RNA interference to automatically disable the function of individual human genes and prevent the formation of the respective proteins. In the laboratory, human cells can be infected with influenza viruses and the reproductive capacity of the viruses tested. This systematic approach has enabled Max Planck researchers Alexander Karlas, Nikolaus Machuy and Thomas F. Meyer (and other colleagues) to track down a total of 287 human cellular factors involved in virus reproduction from approximately 24,000 genes in the human genome.
Many of the identified proteins were indispensible for the replication of a broad-spectrum of influenza virus types, including the new pandemic H1N1 virus. Working in cooperation with Thorsten Wolff from the Robert Koch Institute, the scientists also discovered that these identified proteins were critical for the replication of the highly pathogenic H5N1 influenza viruses (“avian flu viruses”).
Possible applications for the treatment of influenza
The newly-discovered host cell factors, which are essential to the emergence and progression of influenza infections, are now being further researched at the Max Planck Institute. The long-term aim is the development of drugs that will block these host cell factors without triggering any significant side effects. The researchers assume that such innovative virostatic agents are unlikely to give rise to resistance development by the viruses, and will also prove effective against hitherto unknown influenza subtypes.
It is also conceivable that the identified human genes themselves could be impeded using the RNA interference method. The systematic study of such therapeutic applications using RNA interference in Europe began as far back as 2004 with the establishment of the European research partnership RIGHT, coordinated by Professor Meyer. The 2006 Nobel Prize-winning technology may therefore not only be useful for the characterisation of infection-relevant human genetic functions but also as a therapeutic application. This aspect of the technology has also been recognised by the pharmaceutical companies with which the Institute maintains contact.
RNA interference offers enormous potential for combating infectious diseases
Based on the increasing recognition of the fact that infection and its progression are dependent on the contributions of the two parties involved – host and pathogen – novel options for the treatment of acute and chronic infections are emerging. “Together with the use of antibiotics and vaccines, the strategy involving the targeted silencing of human genes at particular times will also play an important role in combating infectious diseases in the future,” says Professor Thomas Meyer, Director of the MPI in Berlin and head of the research group. “Although the switching-off of human gene functions may appear problematic at first, the same principle has been used successfully for decades in the drug-based treatment of other diseases, from cancer to headaches. So what prevents us from applying the same approach against infectious diseases?”
Alexander Karlas, Nikolaus Machuy, Yujin Shin, Klaus-Peter Pleissner, Anita Artarini, Dagmar Heuer, Daniel Becker, Hany Khalil, Lesley A. Ogilvie, Simone Hess, André P. Mäurer, Elke Müller, Thorsten Wolff, Thomas Rudel and Thomas F. Meyer
Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication
Nature, published online on January 17th, 2009
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