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High-throughput characterization of host promiscuity for precisely designed synthetic viral capsid

Periodic Reporting for period 1 - Hi-SynVir (High-throughput characterization of host promiscuity for precisely designed synthetic viral capsid)

Reporting period: 2015-07-01 to 2017-06-30

"The world is facing complex challenges: global warming, ecosystem fragilization, systemic pollution and demographic expansion. The demand in food supply will increase by half in the next 15 years. Achieving higher food production at lower environmental cost is therefore a pressing necessity. Concomitantly, pests and disease vectors are becoming increasingly resistant to otherwise costly, polluting chemical pesticides. Traditional geographic ranges of such pests are altered by globalization and climate change, resulting in emerging threats for natural ecosystems, agriculture and human health. It is urgent to improve our ability to swiftly develop targeted solutions to contain such threats, while minimizing unintended side effects on the environment.
The use of entomopathogenic viruses for the biological control of agronomical insect pests and disease-vectors has been proposed as an alternative strategy to chemical control since the 1970's. This project was driven by increasing resistance of ""harmful"" insects to chemicals and the beginning of societal eco-aware expectation. Today, developing biocontrol is a crucial challenge and basic research on specificity is needed to ensure the safety of such an endeavor.
Parvovirinae are small animal viruses found in vertebrates (parvoviruses) and invertebrate (densoviruses). These viruses have proven valuable tools for gene therapy and are attracting considerable attention as potential biocontrol agents against insect pests. Indeed, densoviruses can be highly pathogenic for a large variety of arthropods, including phytophagous caterpillars and grasshoppers, as well as disease vectors of plants and mammals such as aphids and mosquitoes. Densovirus Infections are generally lethal, though the symptoms vary from host to host; one densovirus has been shown to confer protection against other pathogens to its caterpillar host. What determines densovirus specificity is generally unknown, host ranges appear to vary considerably amongst even closely related densoviruses. A better understanding of the molecular mechanisms underlying virulence and specificity is necessary to evaluate the risk and opportunities associated with potential biotechnological use.
We propose to discover these determinants through the use of synthetic biology to generate high-throughput implementation of model densoviruses and study their selection in insect models, several speices of caterpillars and mosquitos. The scale of this approach will permit to reconstitute the sequence-structure-activity relationships required to relate viral genomes to host specificity and propagation efficiency. Eventually, this will support the development of models to predict the behavior of a viral genome in a new ecology, assess its potential for future evolution and inform the safe use of vectors for the targeted biocontrol of insect populations.

The Hi-Syn-Vir project started the 1st of July 2015 and ended the 30th of September 2015, because I was hired as a permanent researcher by the INRA institute. During the three months of my fellowship, I devised a medium-scale approach to build the experimental pipeline described in the project. I designed a method to introduced targeted mutations with a well-defined rate and I endeavored to construct plasmid vectors necessary to introduce these mutations in the genome of a model densovirus used in the lab. I constructed and validated a intermediate constructs although at this point, I troubleshot a major technical roadblock that made me change the strategy and choose for a heavier molecular approach although less risky.

In conclusion, the MSCA fellowship was a successfull jumpstart. I have since been able to successfully implement the strategy and carry on with the development of the project. Although finally restricted to 3 months, the support of the MSCA fellowship allowed me to successfully jumpstart the Hi-SynVir project. This project is now continued in the DGIMI lab at the University of Montpellier where I got an INRA researcher position.
By providing an extensive mapping of the densovirus sequence-structure-activity relationships this project will lay the foundation of an ambitious framework to i) experimentally assess the potential of a given viral genome for future evolution; ii) support the development of models to predict its behavior when exposed to new host environments; iii) evaluate the use of natural or engineered viral agents for controlling insect populations; iv) scrutinize surveillance metaviromic data and monitor risks for host shifts or the emergence of new pathogens.
The use of genetically engineered organism for controlling natural population is not allowed under current European regulations. This might change in the future. Large-scale functional screening of capsid variants can lead to applications that do not involve genetically modified viruses. Moreover, applications are not restricted to insects. In fact, closely related adeno-associated viruses are actively used for gene therapy . Applications in this area are perfectly conceivable given that we are planning to screen human cell lines along with that of insects.
The host institution is strongly committed to translational research and has efficient services to assist in the filling of patents.