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

Organisms use constitutive or induced defenses against pathogens and other external threats. Constitutive defenses are constantly on, whereas induced defenses are activated when needed. Each of these strategies has costs and benefits, which can affect the type of defense that evolves in response to pathogens. In addition, induced defenses are usually regulated by multiple negative feedback mechanisms that prevent overactivation of the immune response. However, it is unclear how negative feedback affects the costs, benefits, and evolution of induced responses. To address this gap, we developed a mechanistic model of the well-characterized Drosophila melanogaster immune signaling network that includes 3 separate mechanisms of negative feedback as a representative of the widespread phenomenon of multilevel regulation of induced responses. We show that, under stochastic fly-bacteria encounters, an induced defense is favored when bacterial encounters are rare or uncertain, but 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, linking negative feedback mechanisms to the factors that favor induction.