Since 2005, the Bettencourt Schueller Foundation has been a partner of Inserm’s Avenir program. In 2009, it also partnered with the CNRS ATIP program, which helps top-level young researchers with outstanding research projects who wish to create their own team and return or move to France. The ATIP-Avenir program has become synonymous with excellence, providing a springboard for members to obtain further financing. The grant amounts to 300,000€. Since the Foundation joined the program, 11 such grants have been awarded to eight French researchers returning to France and three researchers from other countries settling in France. Five of their teams are based in Paris, three in Bordeaux, two in Toulouse and one in Montpellier.
Juan Reguera is being sponsored by the Foundation to create his own team at AFMB (architecture and function of biological macromolecules laboratory) in Marseille. On the program: the molecular dissection of viral replication mechanisms.
In 1952, the Chikungunya virus was identified for the first time in Tanzania. Some 61 years later, it made its first appearance on American soil. The cause of this sudden spread was human travel and climate change, which created favorable conditions for the vector of the disease, Aedes mosquitoes. Rarely fatal, the infection causes joint pain that can become chronic.
Sponsored by the Foundation to create his team in Marseille, Juan Reguera wants to further scientific knowledge on the processes involved in replicating viral genetic material. Up until now, most research has focused on one or two key sites of the enzymes involved. Juan Reguera wants to see the replication complex in its entirety. The Chikungunya virus stores its genome in RNA. Using structural biochemistry techniques, the researcher observes the way in which the polymerases that synthesize the new RNA from the viral genomic RNA interact with other enzymes that cut, cover or add methyl groups.
By explaining the three-dimensional structure of this set of proteins, Juan Reguera will be able to determine how the individual catalytic domains are combined and regulated during the infection and how this machinery recognizes the viral RNA. The young research team will then design tiny molecules to counter these newly revealed Chikungunya replication and transcription mechanisms.
Juan Reguera is passionately interested in viral structures. His doctoral thesis concerned the spherical mouse parovirus, which stores genomic information on DNA. Then he worked only with RNA viruses, including the SARS coronavirus, which appeared for the first time in China in 2002. His work alongside Stephen Cusack at the European Molecular Biology Laboratory (EMBL) in Grenoble enabled him to develop a full range of strategies to explain the three-dimensional structure of large protein complexes. For example, he combined widespread protein expression, electron cryomicroscopy, X-ray crystallography, and comparisons of homologies and proteomics data. He thus determined the 3D structure of the RNA-dependent RNA polymerase of the La Crosse bunyavirus, responsible for human encephalitis. In particular, the structure reveals four tunnels for the viral RNA, messenger RNA and nucleotides. The information obtained explains the functioning of all negative-sense RNA viruses.