Thèse Déterminants Génétiques Humains et Viraux de la Susceptibilité à la Dengue H/F - Doctorat.Gouv.Fr

Établissement : Université de Montpellier École doctorale : Sciences Chimiques et Biologiques pour la Santé Laboratoire de recherche : MIVEGEC - Maladies Infectieuses et Vecteurs : Ecologie, Génétique, Evolution et Contrôle Direction de la thèse : VINCENT PEDERGNANA ORCID 0000000278525339 Début de la thèse : 2026-10-01 Date limite de candidature : 2026-05-11T23:59:59 Notre compréhension des mécanismes de pathogénicité des agents infectieux reste limitée malgré des années de recherches. Des
facteurs génétiques humains et microbiaux ont été associés au risque de développer une maladie infectieuse. Cependant très peu
d'études se sont intéressées aux variations dans les deux organismes de façon simultanée alors même que l'hôte et le pathogène
déterminent de façon conjointe l'issue d'une infection. En testant simultanément les associations entre le génome d'un pathogène et de
son hôte, ce projet vise à identifier lensemble des interactions hôte-pathogène et à estimer leur rôle dans le développement d'une
maladie due au virus de la dengue, l'infection transmise par un moustique la plus fréquente. La compréhension complète de ces
interactions hôte-virus permettra d'identifier les patients à risque de développer une maladie. Dengue virus (DENV) is a mosquito-borne flavivirus. It is the most common arboviral disease, with 40% of the world's population living in
areas of DENV transmission, and an estimate of 400 million annual infections. Moreover, the geographical expansion of vector-borne viral
diseases like dengue is increasing, with for example, several indigenous cases of dengue reported in the South of France since 2014, or
dengue becoming endemic in La Réunion since 2018. Infections with DENV can result in a wide spectrum of clinical manifestations,
ranging from asymptomatic infection to the debilitating acute febrile illness, dengue fever, and the life-threatening severe dengue,
formerly designated as dengue haemorrhagic fever/dengue shock syndrome. Currently, dengue prevention relies solely on vector
(mosquito) control, which has not resulted in sustainable reduction in infection and disease incidence. Vaccine development has made
major improvement recently in the wake of tetravalent chimeric vaccines, such as Dengvaxia®, or QDenga®. However, vaccination could
lead to an increased risk for severe dengue disease due to a phenomenon termed antibody-dependent enhancement; such that the WHO
recommends that Dengvaxia® should not be licensed to individuals who have not been previously infected with wild DENV.
Mots clés - Keywords
Thématique / Domaine / Contexte
Why are some host individuals susceptible to develop infection by DENV and develop severe phenotypes and others not? Understanding
the genetic characteristics of genes driving host-pathogen interactions is crucial to better understand dengue pathogenicity. There is
some evidence that viral or host factors can influence dengue pathogenesis. However, there are few genetic association studies on DENV
infection, even when considering one of the two actors alone and not the interaction. More than ever, a comprehensive understanding of
human-dengue interactions is needed to tackle the threat caused by DENV infection. The main goal of this PhD is to identify new genes in the host and the virus genomes to better understand dengue pathogenicity. We
propose to apply new genetic analysis techniques that Dr Pedergnana has recently developed to identify at the same time more
important interactions between DENV and human genomes. This approach represents a significant improvement over current approaches
by integrating both interacting organisms' genomes in the same analysis. It allows to bypass the need for clinical phenotypes in genome
wide association studies to uncover important genes related to infections aetiology. For this project, Dr Pedergnana has established
collaborations to study three cohorts of dengue-infected patients from Sri Lanka, La Réunion and Singapore. Specific objectives are
detailed in each of two subprojects below. Dr Pedergnana developed a genomic approach aimed at exploring the interactions between pathogen genome and its host genome
(GxG) in the context of hepatitis C virus infection. As pathogen and host jointly determine disease phenotypes (i.e. symptoms), no genetic
variant in either of these populations should be considered harmful without incorporating the other into the context. This approach allows
to explore directly the relationships between both genomes but also between genomes and phenotypes of interest in Natura. In brief, this
method is based on performing regression models and takes into account the human and viral population structures by including viral
and host principal components as covariates. It allows the characterization of the genetic architecture of virus-human interactions; that is
the number of interactions, their physical locations in their respective genomes and their corresponding effect.
For this project, we will also explore other statistical methods that we have recently proposed using infection matrix, which captures the
extent to which each pathogen genotype successfully infects each host genotype or have been developed by colleagues using mixed
effects models or Bayesian.

Compétences attendues et/ou qui devront être développées au cours de la thèse :
-bio-informatique : analyse de données omiques.
-analyse phylogénétique
-analyses statistiques
-lecture régulière d'articles et rédaction d'articles scientifiques.
-participation et contribution à la vie scientifique de l'équipe.
-forte motivation et véritable intérêt pour l'épidémiologie et la génomique quantitative.