IMD-mediated innate immune priming increases Drosophila survival and reduces pathogen transmission

Invertebrates lack the immune machinery underlying vertebrate-like acquired immunity. However, in many insects past infection by the same pathogen can ‘prime’ the immune response, resulting in improved survival upon reinfection. Here, we investigated the mechanistic basis and epidemiological consequences of innate immune priming in the fruit fly Drosophila melanogaster when infected with the gram-negative bacterial pathogen Providencia rettgeri. We find that priming in response to P. rettgeri infection is a long-lasting and sexually dimorphic response. We further explore the epidemiological consequences of immune priming and find it has the potential to curtail pathogen transmission by reducing pathogen shedding and spread. The enhanced survival of individuals previously exposed to a non-lethal bacterial inoculum coincided with a transient decrease in bacterial loads, and we provide strong evidence that the effect of priming requires the IMD-responsive antimicrobial-peptide Diptericin-B in the fat body. Further, we show that while Diptericin B is the main effector of bacterial clearance, it is not sufficient for immune priming, which requires regulation of IMD by peptidoglycan recognition proteins. This work underscores the plasticity and complexity of invertebrate responses to infection, providing novel experimental evidence for the effects of innate immune priming on population-level epidemiological outcomes.Author summary: When we are vaccinated, our immune response is able to respond quickly if we are ever exposed to the same pathogen in the future. Unlike humans, the immune systems of invertebrates, such as insects, are not capable of the same type of specific immune memory. However, much work has shown that insects previously exposed to an inactivated pathogen will fare better if they are re-infected–a phenomenon broadly called “immune priming”. How insects are able to do this is an exciting focus of current research. We investigated immune priming in the fruit fly, a powerful model system for infection and immunity. We found that exposure to an inactivated form of the bacterial fly pathogen Providencia rettgeri resulted in flies better surviving a subsequent live infection. This effect lasted several days, was stronger in male flies, and was seen in different fly genetic backgrounds. We uncovered that priming requires a specific immune response in the fly fat-body (the equivalent to a fly ‘liver’) that produces an antimicrobial protein called Diptericin. We also found that primed flies were able to keep pathogen growth lower, and that this reduced their ability to spread the infection to other flies.