The role of uncertainty and negative feedback loops in the evolution of induced immune defenses

Organisms use constitutive or induced defenses against pathogens, parasites, and herbivores. Constitutive defenses are constantly on, whereas induced defenses are activated upon exposure to an enemy. Constitutive and induced defenses each have costs and benefits, which can affect the type of defense that evolves in response to pathogens. Previous models that compared the two lacked mechanistic details about host defense, did not consider pathogen proliferation rates, or lacked both features. To address this gap, we developed a detailed mechanistic model of the well-characterized Drosophila melanogaster immune signaling network. We evaluated the factors favoring the evolution of constitutive and induced defenses by comparing the fitness of each strategy under stochastic fly-bacteria interactions. We show that an induced defense is favored when bacteria are at low density, heterogeneously distributed, or have fluctuating distributions in ways that depend on the bacterial proliferation rate. Our model also predicts that the specific negative regulators that optimize the induced response depend on the bacterial proliferation rate. We therefore conclude that an induced immune defense is favored in environments where bacterial encounters are uncertain—because of heterogeneity in spatial or temporal distributions—but that benefit depends on the mechanism of induction and pathogen properties.