(Vienna, 18 July 2012) Scientists in the research group of the Scientific director Giulio Superti-Furga at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences succeeded in describing and identifying the weak points of the molecular network that human cells utilize against viruses. Results from the comparisons of the attacking strategies of 30 known viruses were published as an advanced online publication on July 18, 2012 in Nature. The insights can provide the basis for further investigations targeted towards the development of new antiviral therapies.
Viruses are not complete cells. They are obliged to invade cells in order to use them for their purposes. They use the molecular machinery of the host cells as well as the cellular proteins and their complex interactions in order to synthesize their genetic information, to duplicate and to multiply. For this to succeed, viruses face the challenge of escaping from the cell’s defense mechanisms. Due to their limited genetic material, viruses must be both parsimonious and efficient. To outsmart the cellular defense mechanisms, they use the camouflage strategy; they disguise themselves in order to go unnoticed. Another tactic they use is to manipulate the signaling pathway of the cell’s defense so it does not cause alarm. Previous scientific studies were focused on the investigation of single viruses and typically elucidated individual strategies. In a completely novel approach, this study led by Andreas Pichlmair in the team of Giulio Superti-Furga, Scientific Director of CeMM, looked at viruses for the perspective of the human cell and simultaneously examined 30 different viruses for their ways to sabotage the cellular security plan.
Giulio Superti-Furga, responsible for this large study, said: “Figuratively speaking, we have left the enemy inside the kingdom in order to identify the vulnerabilities and the most important switches in our intracellular defense system”. Altogether, the study reveals two viral attack strategies: on the one hand interrupting the internal cell communication and coordination processes and on the other hand controlling and specific pathways. At the same time, there are ‘hotspots’ and ‘molecular junctions’ that are attacked by many different viral proteins. One such junction is the RNA-binding hnRNP-U, a key antiviral defense protein that viruses like Flu, Hepatitis C, as well as Herpes use as a target. Another example is one protein of the Smallpox virus that inactivates specific cellular kinases that take part in the regulation of the central NF-Kappa B system, as well as a protein of the Hepatitis C virus that controls the degradation of cellular proteins.
Comparing the activity of all tested viral proteins and allocating them to the different viral groups according to the genomic structure (single- or double-stranded RNA viruses or DNA viruses), it becomes evident which viruses use common and which use unique attacking strategies and in many instances but not always, related viruses deploy related operation modes. This study enables the future classification of viruses according to their cellular target molecules and through this the development of novel therapeutic approaches.
The study was mainly supported by an ERC Advanced Investigator Grant from Giulio Superti-Furga and an EMBO Long-Term-Fellowship from Andreas Pichlmair.