The Genetic Architecture of Defense as Resistance to and Tolerance of Bacterial Infection in Drosophila melanogaster

Defense against pathogenic infection can take two forms: resistance and tolerance. Resistance is the ability of the host to limit a pathogen burden, whereas tolerance is the ability to limit the negative consequences of infection at a given level of infection intensity. Evolutionarily, a tolerance strategy that is independent of resistance could allow the host to avoid mounting a costly immune response and, theoretically, to avoid a coevolutionary arms race between pathogen virulence and host resistance. Biomedically, understanding the mechanisms of tolerance and how they relate to resistance could potentially yield treatment strategies that focus on health improvement instead of pathogen elimination. In order to understand the impact of tolerance on host defense and identify genetic variants that determine host tolerance, we defined genetic variation in tolerance as the residual deviation from a binomial regression of fitness under infection against infection intensity. We then performed a genome-wide association study (GWAS) to map the genetic basis of variation in resistance to and tolerance of infection by the bacterium Providencia rettgeri. We found a positive genetic correlation between resistance and tolerance and we demonstrated that the level of resistance is highly predictive of tolerance. We identified 30 loci that predict tolerance, many of which are in genes involved in the regulation of immunity and metabolism. We used RNAi to confirm that a subset of mapped genes have a role in defense, including putative wound repair genes grainy head and debris buster. Our results indicate that tolerance is not an independent strategy from resistance, but that defense arises from a collection of physiological processes intertwined with canonical immunity and resistance. This article is protected by copyright. All rights reserved.