Drosophila immune priming to Enterococcus faecalis relies on immune tolerance rather than resistance.

Innate immune priming increases an organism's survival of a second infection after an initial, non-lethal infection. We used Drosophila melanogaster and an insect-derived strain of Enterococcus faecalis to study transcriptional control of priming. In contrast to other pathogens, the enhanced survival in primed animals does not correlate with decreased E. faecalis load. Further analysis shows that primed organisms tolerate, rather than resist infection. Using RNA-seq of immune tissues, we found many genes were upregulated in only primed flies, suggesting a distinct transcriptional program in response to initial and secondary infections. In contrast, few genes continuously express throughout the experiment or more efficiently re-activate upon reinfection. Priming experiments in immune deficient mutants revealed Imd is largely dispensable for responding to a single infection but needed to fully prime. Together, this indicates the fly's innate immune response is plastic—differing in immune strategy, transcriptional program, and pathway use depending on infection history. Author summary: Most animals, like the fruit fly Drosophila melanogaster, lack an adaptive immune system and react to infection using only an innate immune response. In this paper, we study how previous infection with the bacterium Enterococcus faecalis changes the immune response to a second infection with the same bacterium, through a phenomenon called immune priming. We find that primed flies tend to survive more, tolerate a higher bacterial load, and undergo priming-specific gene expression reprogramming compared to non-primed flies. We also find that eliminating a key component of the Imd pathway, which is not canonically related to response to E. faecalis lowered priming ability in flies. These experiments highlight the true complexity of fly immune response and provide a basis for further exploring the interrelatedness of multiple known innate immune pathways in regulating a complex phenomenon like immune priming. [ABSTRACT FROM AUTHOR]