Infection by the Chikungunya virus (CHIKV) has reached pandemic levels owing to the spread of its vectors, Aedes aegypti and Aedes albopoctus. It’s accompanied by a high morbidity, with half of the infected patients being incapacitated in the long run. In its acute form, CHIKV causes Chikungunya fever (CHIKF), a dengue-like illness characterised by the combination of fever, rash, headache and arthralgia. CHIKF was formerly known to be non-fatal and self-limiting but its re-emergence has increasingly been associated with persistent and incapacitating manifestations, mainly in the rheumatologic and neurologic spheres. CHIKV thus constitutes — with several other arboviruses (arthropod-borne viruses) such as dengue and the recently emerging Zika virus — a major public health concern worldwide.
The molecular and genetic determinants of CHIKV infection responsible of its chronic manifestations are still poorly understood. Whether these manifestations could be the consequences of a persistent CHIKV infection or the residual sequelae of an acute reversible disease is still hotly debated. Finally, there is no treatment nor vaccine available to overcome the burden of such disabling disease. Although recent developments have spurred investigations into the virus adaptation to new vectors, these studies do not allow to explore new biomedical solutions. This project proposes to undertake a host genomics approach (high-throughput genotyping, and transcriptome) to identify the genetic factors of resistance/susceptibility against infection or against persistent manifestations, in order to better understand the molecular mechanisms at stake and allow the rational development of new diagnostic or therapeutic approaches. This project is made possible by the existence of a unique, very well-characterised cohort (SEROCHIK/TELECHIK) of CHIKV-infected patients available at the CHU La Reunion.
First, we plan to perform a genome-wide association study comparing three main groups: 225 asymptomatic subjects post-infection, 225 patients suffering from persistent manifestations post-infection, and 150 non-infected control subjects. Second, we plan to compare the gene expression patterns in peripheral blood monocytes in two groups of 100 patients issued from the precedent groups. Using an integrative approach, developed within the GBA Laboratory, based on individual SNPs, haplotypes, eQTLs, and pathway analysis (systems biology), this project will identify the molecular factors that enable or, conversely, prevent infection by CHIKV or maintain a long-lasting inflammation following infection. Similar correlation analyses will be performed on gene expression in each group, and functional data associating genotypes and transcriptome will be obtained. These results will lead to a better understanding of the molecular mechanisms underlying CHIKV infection and its long-term sequelae, and as a consequence they will pave the way for personalized medicine, ie, the rational development of new diagnostic/therapeutic solutions.
This would be the first major genetic study using a large-scale genomic approach proposed to understand the molecular aetiology of CHIKV infection, with 10 years of medical hindsight, at a time when dramatic resurgences could occur. It is badly needed since no treatment nor vaccine are yet available to fight the disease and its long-term consequences. The teams involved in this project have proven their expertise in the fields of CHIKV infection, human host genetics, and bioinformatics, and they clearly master all the technologies needed to accomplish the project.
Monsieur Jean-François Zagury (GÉNOMIQUE, BIOINFORMATIQUE ET APPLICATIONS)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
GBA GÉNOMIQUE, BIOINFORMATIQUE ET APPLICATIONS
CHU de La Réunion Centre hospitalier universitaire de La Réunion
PIMIT UMR 134 Processus Infectieux en Milieu Insulaire Tropical, Université de La Réunion, INSERM U 1187, CNRS 9192, IRD 249, Reunion island, France
Help of the ANR 573,936 euros
Beginning and duration of the scientific project: September 2016 - 36 Months