Deadline for full application: December 15th, 2013
Interviews: March, 2014
Start of the Ph.D.: October 1st, 2014
Title of the PhD project: RNA virus nucleotide composition, virus attenuation and immune response
Name of the lab: Populations virales et pathogenèse
Head of the lab: VIGNUZZI, Marco
PhD advisor: VIGNUZZI Marco
Email address: firstname.lastname@example.org
Web site address of the lab: www.vignuzzilab.eu
Doctoral school affiliation and University:
Presentation of the laboratory and its research topics: The Vignuzzi lab (Viral Populations and Pathogenesis Unit) studies the molecular biology and evolution of RNA viruses. Members of our group study how viral polymerases process RNA and contribute to mutation rates, how RNA viruses are affected and react to antiviral compounds, how RNA genomes can be manipulated to alter virus fitness, and how deep sequencing and experimental evolution can be used to monitor virus adaptation and evolvability.
Description of the project:
(1 page, Arial font size 11 : 600 words in total with at least 50% dedicated specifically to the PhD project(s))
Since RNA viruses have extreme mutation frequencies, we have studied the molecular mechanisms responsible for, and the consequences of, altering these intrinsic mutation rates. Our lab has generated numerous mutator (higher mutation frequency than wildtype) and antimutator (lower mutation frequency) strains of picornaviruses and alphaviruses. For antimutator viruses, we observe attenuation in vivo resulting from an inability to adapt and change during infection, a possible inability to counter the resulting immune responses. For mutator viruses, our studies suggest that the observed in vivo attenuation is the result of a high error rate coupled to reduced population sizes occurring when viruses undergo population bottlenecks in vivo. Much of our attention has focused on how the virus' intrinsic error rate may reduce fitness in vivo and result in attenuation, but we have not examined specifically how the host immune response might react to virus populations presenting more or fewer mutations. The questions remain as to whether a highly mutated population (mutator) would result in a more broad immune response or whether a very homogenous and pure population (antimutator) would permit more specific immune reponses. Answers to these questions may allow us to rationally alter virus genomes to maximize their immunogenic potential. In the context of this PhD project, the student will examine how a virus population presenting higher or lower mutation frequencies may be differently sensed by the innate immune system, both in the context of a primary infection, as well as an infection followed by challenge (immunization). S/he will also determine whether antigenicity is similarly affected by differences in mutational load. The candidate will determine whether a bias for certain mutations will have a greater impact on immune sensing. Finally, the candidate will use this information to rationally attenuate viruses by altering their nucleotide composition and determine the impact in both a fundamental (evolution of viruses) and applied (development of vaccines) sense.
1. Levi, L.I., Gnadig, N.F., Beaucourt, S., McPherson, M.J., Baron, B., England, P., Arnold, J.J., Vignuzzi, M. (2010) Fidelity variants of RNA dependent RNA polymerases uncover an indirect, mutagenic activity of amiloride compounds. PLOS Pathogens 6(10): e1001163.
2. Coffey, L.L., Beeharry, Y., Bordería, A.V., Blanc, H. and Vignuzzi, M. (2011) Arbovirus high fidelity variant loses fitness in mosquitoes and mice. Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):16038-43.
3. Gnädig, N.F., Beaucourt, S., Campagnola, G., Bordería, A.V., Sanz-Ramos, M., Gong, P., Blanc, H., Peersen, O., Vignuzzi, M (2012). Coxsackievirus B3 mutator strains are attenuated in vivo. Proc Natl Acad Sci U S A. 2012 Aug 21;109(34):E2294-303.
virus evolution, mutation rates, genetic robustness, attenuation, viral immunity
Expected profile of the candidate (optional):