Immunological and genetic determinants of the response to Ebola virus infection – EBOIMGEN

Variability in response to Ebola virus (EBOV) exposure and infection is now well-established. In particular, it was found that exposure to EBOV could result in asymptomatic or pauci-symptomatic infections, and that some highly exposed individuals could be considered as non-infected. Based on these observations, in this proposal, we formulate two main hypotheses: (1) human genetic factors play key roles in the response to EBOV infection through the control of infection after exposure and the control of pathogenesis after infection, and (2) the fine dissection of antibody profiles in healthy infected individuals and disease survivors will help understanding and defining correlates of protective immunity against EBOV infection. It takes advantage of three unique cohorts of survivors and contact persons of Ebolavirus disease (EVD) cases during the 2014-2016 and 2018-2020 EBOV outbreaks in Guinea and the Democratic Republic of Congo (DRC), respectively, established by the coordinator of the proposal. To test our hypotheses, the project is organized in two specific objectives. The first is to search for human genetic variants strongly influencing resistance to EBOV infection and those predisposing to the development of the clinical diseases using whole exome sequencing (WES) studies. Cutting edge methods will be used to analyze the WES data in three groups of individuals from the Guinean cohort: 50 highly exposed non infected contacts, 50 infected asymptomatic/pauci-symptomatic contacts, and 50 EVD survivors. These analyses will then be replicated on samples collected within the DRC cohort. The second objective is to characterize the antibody repertoires of 300 EVD survivors at inclusion, during the follow up and the final visit and in infected asymptomatic/pauci-symptomatic contact persons of EVD cases. We will use multiple antibody profiling (xMAP). We will in particular test the evolution with time of specific IgG titers and average affinities by SPR (Surface Plasmon Resonance), of the different IgG isotypes and their association with clinical severity (eg late complications) with IgG levels. Preliminary results regarding WES analyses of a first sample of 60 subjects and the evolution with time of total IgG antibodies in 543 Guinean survivors are very promising. This ambitious project is highly innovative and feasible due to the complementarity and strong expertise of the two partners in their respective fields. It will provide a refined dissection of the antibody responses among subjects who were naturally infected (with or without clinical symptoms) allowing a much better understanding of the immunological responses to EBOV infection. It should also provide new insights in the mechanisms of resistance to EBOV infection in natural conditions of infection, as well as in the pathways involved in the development of clinical disease in infected subjects. These results could open new avenues regarding the prevention of EBOV infection, and the development of novel candidate vaccines.