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

Most multicellular organisms, including fruit flies, possess an innate immune response, but lack an adaptive immune response. Even without adaptive immunity, "immune priming" allows organisms to survive a second infection more effectively after an initial, non-lethal infection. We used Drosophila melanogaster to study the transcriptional program that underlies priming. Using an insect-derived strain of Gram-positive Enterococcus faecalis, we found a low dose infection enhances survival of a subsequent high dose infection. The enhanced survival in primed animals does not correlate with a decreased bacterial load, implying that the organisms tolerate, rather than resist the infection. We measured the transcriptome associated with immune priming in the fly immune organs: the fat body and hemocytes. We found many genes that were only upregulated in re-infected flies. In contrast, there are very few genes that either remained transcriptionally active throughout the experiment or more efficiently re-activated upon reinfection. Measurements of priming in immune deficient mutants revealed IMD signaling is largely dispensable for responding to a single infection, but needed to fully prime; while Toll signaling is required to respond to a single infection, but dispensable for priming. Overall, we found a primed immune response to E. faecalis relies on immune tolerance rather than bacterial resistance and drives a unique transcriptional response.