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Oral administration of heat-killed Mycobacterium manresensis induces an increased response against subsequent infections in the Drosophila melanogaster model

M Cortacans(1,2,3,4) M Arch(1,2,3,4) E Fuentes(1,2,4) P J Cardona(1,2,3,4,5)

1:Experimental Tuberculosis Unit (UTE), Institut de Recerca Germans Trias i Pujol (IGTP), Badalona (08916), Spain; 2:Servei de Microbiologia, LCMN, Hospital Universitari Germans Trias i Pujol (HUGTiP), Badalona (08916), Spain; 3:Microbiology and Genetics Department, Universitat Autònoma de Barcelona (UAB), Bellaterra (08193), Spain; 4:Centre de Medicina Comparativa i Bioimatge de Catalunya (CMCiB), Badalona (08916), Spain; 5:Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid (28029), Spain

Drosophila melanogaster has shown to be a good experimental model to study tuberculosis (TB) using Mycobacterium marinum infection, since flies have homology in 75 % of disease-causing genes in humans and a complex immune system that relies solely on innate immune responses. Mycobacterium manresensis is an environmental mycobacteria that has previously demonstrated high pathogenicity in D. melanogaster. This study explored the hypothesis that oral administration of low doses of M. manresensis induces the long-term reprogramming of innate immune cells, leading to the establishment of the trained immunity phenomenon. This premise was tested by systemically infecting flies with pathogenic M. marinum, Staphylococcus aureus, and Candida albicans after 24- and 48-hour oral treatments with heat-killed M. manresensis (hkMm). Gene expression analysis exhibited that the mere presence of the environmental mycobacteria enhanced the flies’ immune response 72 hours after the end of the treatment regimens, leading to an increased response when encountering subsequent challenges. Pathogen load analysis revealed that treatment administration induces a significant reduction in pathogen load in the S. aureus and C. albicans infection groups in a dose- and sex-dependent manner, indicating a possible increase in resistance to infection in treated flies. Conversely, pathogen load increased in M. marinum infection groups, suggesting an increase in tolerance in treated flies since higher CFU counts did not result in higher fly mortality. Hence, the provided data suggest that oral administration of hkMm provides unspecific protection against subsequent infections by modulating the innate immune response of the host.

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