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Résumé:

The chikungunya virus (CHIKV) belongs to Alphavirus genus which can be found in an ecological but not taxonomic group named arboviruses (for arthropod-borne viruses) indicating viruses transmitted by an arthropod vector hematophagous to a vertebrate host, during a blood meal. Alphaviruses are transmitted by bloodsucking arthropods, mainly mosquitoes, to humans and animals causing debilitating disease. While in human CHIKV disease is characterized by fever, headache, and a typical acute infection, sometimes followed by persistent arthralgia or myalgia, the infection does not seem to cause significant pathology in mosquito. The identification of cellular and viral factors involved in the human pathology and mosquito chronicity could allow to develop antiviral treatments. The regulated apoptotic cell death and interferon Type-I immune response are strong antiviral defence participating in rapid viral elimination. Moreover, it has been demonstrated that p53 plays a central role in the regulation of cell death and Type-I interferon signalling pathway during different viral infections.

In this way my work was to study the potential role of p53 and p53 isoforms on cellular outcome and viral infection in mammal and insect infected with Alphavirus, mainly chikungunya virus and to a lesser extent Sindbis virus. First, in order to investigate a potential function of p53 on viral infection in mammal and insect, infected with chikungunya virus and Sindbis virus, we have generated p53 knockout human skeletal muscle cell line. In addition, Drosophila melanogaster p53-/- mutant strain were injected with viruses. We observed an opposite effect of p53 knockout on chikungunya virus infection in in vitro human cells and in vivo in Drosophila melanogaster. Secondly, p53 gene leads to several different protein isoforms which participate to p53 regulation through transcriptional and translational regulatory mechanisms. For my project we have investigated a possible function of ∆40p53 and ∆133p53 isoforms on CHIKV infection. We have set up and carried out (i) human muscle cell line overexpressing endogenous ∆40p53 using CRISPR/Cas9 technology and (ii) an inducible-system overexpressing ∆40p53 or ∆133p53 protein isoforms. We observed that endogenous overexpression of ∆40p53 isoform led to a decrease in CHIKV infection, but the mechanism remains unclear.