A Signaling Protease Required for Melanization in Drosophila Affects Resistance and Tolerance of Infections

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Abstract
Organisms evolve two routes to surviving infections—they can resist pathogen growth (resistance) and they can endure the pathogenesis of infection (tolerance). The sum of these two properties together defines the defensive capabilities of the host. Typically, studies of animal defenses focus on either understanding resistance or, to a lesser extent, tolerance mechanisms, thus providing little understanding of the relationship between these two mechanisms. We suggest there are nine possible pairwise permutations of these traits, assuming they can increase, decrease, or remain unchanged in an independent manner. Here we show that by making a single mutation in the gene encoding a protease, CG3066, active in the melanization cascade in Drosophila melanogaster, we observe the full spectrum of changes; these mutant flies show increases and decreases in their resistance and tolerance properties when challenged with a variety of pathogens. This result implicates melanization in fighting microbial infections and shows that an immune response can affect both resistance and tolerance to infections in microbe-dependent ways. The fly is often described as having an unsophisticated and stereotypical immune response where single mutations cause simple binary changes in immunity. We report a level of complexity in the fly's immune response that has strong ecological implications. We suggest that immune responses are highly tuned by evolution, since selection for defenses that alter resistance against one pathogen may change both resistance and tolerance to other pathogens. To boost its defenses, an organism may increase its resistance to infection by reducing the fitness of the invading pathogen; alternatively, the host may increase its tolerance by reducing the damage caused by a given quantity of pathogen. Melanization is an immune response that has been linked to defense in the fly and other invertebrates. It is expected to cause resistance to infection, as well as host damage mediated by reactive oxygen species generated during melanin production. We demonstrate here that the loss of a gene required for melanization produces a surprisingly complex spectrum of phenotypes, increasing and decreasing both resistance and tolerance to a variety of microbes. For example, increasing resistance to one pathogen can produce corresponding changes in either resistance or tolerance to another pathogen. As a result, there is likely no “best” solution that produces a perfect immune system, only an equilibrium that allows the fly to deal with the pathogenic threats that its ancestors have faced. This equilibrium will require the balancing of both resistance and tolerance, and our study demonstrates that we cannot completely understand the defensive properties of a host unless we measure both of these properties in response to a variety of pathogens.