Description

Classical immunology has long viewed immune systems as lineage-specific innovations, shaped independently in bacteria, plants, fungi and animals. Over the past decade, this view has been challenged by the discovery that several components of eukaryotic innate immunity show clear homology with bacterial immune systems. To describe this phenomenon, our lab introduced the concept of ancestral immunity: immune modules, domains or proteins, that originated in prokaryotes and function in both bacterial and eukaryotic immunity. We recently demonstrated the predictive power of ancestral immunity by showing that immune function in bacteria can be sufficient to predict immune roles in eukaryotes, providing a proof of concept for functional inference across domains of life. To date, however, ancestral immunity has been explored only through isolated examples. Our team developed computational approaches to systematically identify ancestral immune modules in eukaryotes. Building on these results, a small-scale overexpression screen of human candidate genes containing ancestral immune candidate was performed. Among the hits, a family of human kinases stood out for their strong immune signature. These five domains proteins contain a two-domain module (Rossmann-fold+TPR), named below CARal (for Cyclic ADPR Related ancestral module), that originated in bacteria in uncharacterized bacterial defence systems. This project aims to characterize the function and mechanism of the CARal module in diverse bacterial antiphage systems, reconstruct its evolutionary history and diversity across the Tree of Life and study its role and function in eukaryotes.

Aim 1.
Functional and biochemical characterization of the novel module in bacterial antiphage systems. Using sequence similarity searches, the candidate will identify the closest bacterial homologs of the human CARal module and select up to 10 candidates for heterologous expression and antiphage testing in E. coli. Once functional antiphage homologs are validated, biochemical characterization will be performed: the predicted enzymatic activity will be assayed in vitro and in vivo. To understand infection detection, the candidate will evolve phage escapers to pinpoint the trigger. Structural characterization can be pursued through collaboration with the Dinshaw Patel Lab (Sloan Kettering Institute).

Aim 2. Diversity of the CARal module across the Tree of Life.
The candidate will conduct an exhaustive bioinformatics iterative search to capture the full diversity of proteins encoding CARal modules across all domains of life. Using the resulting phylogeny, the candidate will classify newly discovered clades into families based on co-localizing domains, operon structure and defence score in prokaryotes. New CARal architectures will be selected and characterized in vitro for eukaryotic homologs and in vitro and in vivo for following the workflow of Aim 1.

Aim 3.
Informing human immune kinase study. Knowledge gained on bacterial proteins will be applied to human homologs through collaboration with Matthieu Haudiquet and Enzo Poirier (Institut Curie).

Compétences requises

The candidate should hold a Master's degree in molecular biology, microbiology, or a related field. Hands-on experience in molecular cloning, bacterial genetics and microbiology is expected. Experience with heterologous expression systems in bacteria is a strong asset. Familiarity with computational tools for sequence analysis is a plus but can be developed during the PhD with support from the lab's bioinformatics team. The candidate should be curious, motivated to work across experimental and computational approaches, and comfortable in a collaborative environment. Good communication skills in English are required.

Bibliographie

Bernheim, A., Cury, J., & Poirier, E. Z. (2024). The immune modules conserved across the tree of life: Towards a definition of ancestral immunity. PLoS Biology, 22(7), e3002717. https://doi.org/10.1371/journal.pbio.3002717
Cury, J., Haudiquet, M., Hernandez Trejo, V., Mordret, E., Hanouna, A., Rotival, M., Tesson, F., Bonhomme, D., Ofir, G., Quintana-Murci, L., Benaroch, P., Poirier, E. Z., & Bernheim, A. (2024). Conservation of antiviral systems across domains of life reveals immune genes in humans. Cell Host & Microbe, 32(9), 1594–1607.e5. https://doi.org/10.1016/j.chom.2024.08.002
Shomar, H., Georjon, H., Feng, Y., Olympio, B., Guillaume, M., Tesson, F., Cury, J., Wu, F., & Bernheim, A. (2024). Viperin immunity evolved across the tree of life through serial innovations on a conserved scaffold. Nature Ecology & Evolution, 8(9), 1667–1679. https://doi.org/10.1038/s41559-024-02463-z
Bonhomme, D., Vaysset, H., Ednacot, E. M. Q., et al. (2025). A human homolog of SIR2 antiphage proteins mediates immunity via the Toll-like receptor pathway. Science, 389(6758), eadr8536. https://doi.org/10.1126/science.adr8536
Georjon, H., & Bernheim, A. (2023). The highly diverse antiphage defence systems of bacteria. Nature Reviews Microbiology, 21(10), 686–700. https://doi.org/10.1038/s41579-023-00934-x

Mots clés

Evolution, Génomique, Immunité, Mécanismes moléculaires, Systèmes de défense, Bactériophages