Heartwater, caused by Ehrlichia ruminantium (ER) , constitute a major threat to ruminant production in Africa, affecting mainly small ruminants. Although a commercial vaccine is available, it presents so many drawbacks that its use is limited. An efficient, cost-effective and safe vaccine against heartwater to alleviate poverty of smallholder farmers and contribute to a sustainable agriculture in Africa is needed. The inactivated vaccine constitutes the most advanced experimental vaccine against heartwater. The main drawback of any experimental vaccine is the high antigenic diversity of ER strains, limiting its efficacy under field conditions. Our consortium composed of 2 European and 4 African partners propose to tackle this limitation by including a cocktail of strains of different regional genotypes newly isolated within the project. First, the genetic diversity of ER strains from Benin, Burkina Faso, Niger and South Africa, will be assessed during the first two years of the project allowing a follow-up and identification of predominant strain variations circulating over time. New ER strains from different genotypes will be isolated and included in two regional multivalent vaccines. Finally, the efficacy of the inactivated vaccine will be evaluated in field conditions, tested in Burkina Faso and South Africa, respectively, with a new promising oil adjuvant and with a single injection and protection-associated biomarkers will be identify to minimize the need for challenges after any new vaccine trials. Process of production of improved vaccine formulations at industrial level and efficient quality controls will be available at the end of the project. Current project will also allow increasing regional heartwater diagnostic and research capacities. Special efforts will be done to share the research products with stakeholders and end-users such as farmers and local manufacturers.

The project located in Southeast Asia aims at developing scenarios of future health embodied in the One Health approach at the human-animal-environment interface. By investigating the impacts of the intensification of the circulation along the economic corridor (Thailand-Laos) on the evolution of infectious diseases (IDs) of public health interests it intends to: a) integrate ecology and environmental sciences with health sciences and policies; b) foster scientific knowledge integration at various decision levels (regional to local); c) analyze retrospectively and comparatively IDs' dynamics associated to policies, land use and biodiversity changes; d) combine predictive process-based scenarios and policy-driven scenarios of health incorporating disease ecology, biodiversity erosion, future land use and climate changes. Important role will be devoted to ICT Sciences based on a strong partnership between France and Thailand. An integrative data / knowledge base will be created that will include three types of information: a) quantitative data (socio-economics at the village level; infectious diseases including zoonoses; domestic animal populations; resources from wildlife; distributions of precipitation, temperature and impacts of climate change on these variables; soils; agricultural inputs such as pesticides, herbicides and antibiotics); b) a large textual corpus on the strategies and targets to implement international law regionally and nationally and results of text mining to be generated, as well as information on local policy measures and customary law; c) qualitative data obtained from interviews and surveys conducted with decision-makers and community leaders about their representations and perceptions of agriculture, land planning / infrastructure, health and conservation policies. Given their importance in health-environment dynamics, LULC changes will be restored over nearly three decades and projected for the coming decades at various scales (region, habitats, landscapes) by combining various data sources (including satellite products). The interactions between variables and information will be identified and modeled by relying on a variety of tools combining simple correlations (linear or nonlinear), modeling reticular causalities (Bayesian networks), process-based epidemiological models and knowledge representation. The data / knowledge base and models will finally be exploited to produce scenarios combining predictions and story-telling about the likely impacts of strategies and legal and policy measures on health, biodiversity and resource uses (agriculture, LULC, living resources). Scientific evidences gained from the project results will be disseminated among decision-makers and community leaders through workshops and conferences. Indeed those evidences will play a pivotal role in helping decision-makers at different levels to associate socio-ecosystems dynamics and IDs' dynamics, at various spatial scales (villages to districts to transboundary provinces), in their public action.

Since the middle of the 20th century, insecticides have been massively used to control the vectors of infectious diseases and thus limit their impact on public health. This drastic modification of their environment has selected different adaptations in these vectors, collectively referred to as insecticide resistance. The genomic architecture of these adaptations can be very diverse, ranging from simple nucleotide substitutions to large-scale mutations such as gene duplication. The effects of these different mutations on the vectors phenotype and fitness can differ and are difficult to anticipate, particularly in an environment that is itself variable. Using interdisciplinary approaches, the ArchR project aims 1) to understand how these different genomic architectures impact the phenotype of their carriers, and to measure the evolutionary dynamics of multi-copy alleles under various intensities of insecticidal pressure in natura, 2) to study how variations in environmental conditions and the architecture of these adaptive mutations influence the dynamics of genome polymorphism, via the natural selection of resistance alleles and the demographic effects of insecticide treatments, and 3) to measure the effect of mutations on vectorial competence and mosquito metabolism, in order to anticipate their impact on public health. To achieve these objectives, the ArchR project will rely on the wide diversity of resistance alleles with copy number variations found in the Culex pipiens mosquito, and on a unique collection of natural population samples collected over 30 years, combined with quantitative data on insecticide treatment variations. The ArchR project will also rely on a recognized international consortium, which has worked or is already working together on other projects, and which combines the complementary skills (population genetics, genomics and bioinformatics, molecular biology, vector competence and experimental infections, computer modeling, ...) and resources and infrastructure (insectariums level 2 and 3, molecular platforms and computer platforms) necessary to carry out this project. During this project, two PhD and several Master students will also be trained in high-level research with the different partners of this consortium. The ArchR project will thus allow crucial developments for fundamental research in evolutionary biology: early evolution of duplications, impacts of adaptive dynamics on genome evolution, impact of environmental variations on genome polymorphism and population adaptability, evolutionary trade-offs between adaptation and transmission. By linking the treatment practices with their demographic impacts and the dynamics of resistance alleles in natural populations, and by assessing the impact of resistance alleles on mosquito vectorial capacity, it will also provide useful information for professionals in charge of vector control or crop protection, and help design sustainable control strategies.

A fundamental step for the survival and replication of intravacuolar bacterial pathogens is the establishment of a replicative niche inside host cells. This is achieved by secreting bacterial effector proteins in the cytoplasm of the infected cells by specialised secretion systems. Bacterial effector proteins interact with eukaryotic proteins and lipids to manipulate host signalling pathways, thus allowing to escape the host degradative pathway and converge nutrients required for intracellular replication of bacteria. Understanding the host/pathogen interactions that regulate these processes is therefore of prime importance to counter bacterial infections and identify candidate targets for the development of host-targeted antimicrobials, as an alternative to antibiotics. Against the background of host/pathogen interactions, phosphoinositides (PIs) are emerging as targets for a growing number of bacterial effector proteins. These lipids are key player in eukaryotic cell homeostasis, which define the identity of intracellular membranes and serve as regulators of eukaryotic signal transduction. Coxiella burnetii is a class 3 pathogen responsible for the zoonosis Q fever, a debilitating disease with severe health and economic impact. The high infectivity and resistance to environmental stress make Coxiella a potential threat for bioterrorism applications. Key to Coxiella virulence is the Dot/Icm-dependent secretion of bacterial effector proteins that coordinate the biogenesis of a large compartment, the Coxiella-Containing vacuole (CCV). Initially defined as expanded autolysosomes, our recent characterisation of the lipid composition of CCVs suggests that several membrane trafficking pathways of the infected cell are subverted for the biogenesis of these compartments. Importantly, we have observed that perturbing the capacity of Coxiella to manipulate PI metabolism for CCVs biogenesis has in vivo relevance. With this project, we aim at a global characterisation of the Coxiella/PIs interactions with the double aim of 1) characterising the molecular mechanisms regulating the biogenesis of these compartments and 2) target PI metabolism in infected cells to affect Coxiella virulence in vivo. To this aim, we will define the comprehensive lipid profile of CCVs by integrating state-of-the-art microscopy on Coxiella infected cells with lipidomics approaches on isolated CCVs. In parallel, we will identify PI-binding Coxiella effector proteins (PIEs) using PI- and lipid-coated agarose beads. PI/protein interactions will be further investigated using biomimetic membranes of specific lipid composition. The role of Coxiella PIEs in infection will be investigated using bioinformatics approaches coupled to multi-parametric phenotypic screens, taking advantage of our previously generated library of Coxiella mutants. Finally, the in vivo relevance of PIE mutants as well as that of inhibitors of PI metabolism will be established using three independent in vivo models for Coxiella infections. This novel integrative approach will help us drawing a comprehensive map of the PI/Coxiella interactome that orchestrates CCVs biogenesis and identify key interaction hubs for the development of new, tailored antimicrobials targeting the pathogen as well as the host. Of note, our approach developed using C. burnetii as a model pathogen, will serve as a strategic roadmap for the study of other intravacuolar bacterial pathogens.