Summary

Mycolicibacterium manresensis is a fast-growing environmental mycobacterium from the Mycobacterium fortuitum complex that has demonstrated low toxicity in mice and humans. However, recent studies suggest that heat-killed M. manresensis (hkMm) can induce trained immunity, a form of innate immune memory that enhances resistance to infections. Here, we explored its immune-priming potential using Drosophila melanogaster, a powerful model for studying host-pathogen interactions due to its well-characterized innate immune system. We found that oral hkMm treatment significantly restricted the growth of a highly virulent clinical Candida albicans isolate, which otherwise rapidly colonized and killed flies in under 48 hours. HkMm also upregulated antimicrobial peptides, particularly Diptericin, and Drosomycin in males, although it did not extend host lifespan. By demonstrating that oral administration of hkMm can enhance innate immune defences against fungal infections, our work provides new insights into immune training and supports the potential of M. manresensis as a novel immunomodulatory agent.