Six Fundamental Behaviors of Immune-Pathogen Feedback Circuits

Even simple models of interactions between the immune system and pathogens involve nonlinearity, stochastics, and feedback in analog circuits. Here, we show that even the simplest and most fundamental interactions involving the innate immune system, the adaptive immune system, and a pathogenic population in a 3-state dynamical system can lead to six discrete behaviors. These distinct behaviors may be categorized as the initial pathogenic disease state leading to a i) Cure; ii) Death; iii) Resurgence; iv) Chronic Condition; v) Autoimmune Behavior; or vi) Erratic Chaos-like Behavior. We show that the inactivation of strong positive feedback in the immune system when pathogenic populations have subsided is important in ensuring that its strength is not the enemy of calmness. Hence, appropriate sensitivity and reactivity to pathogen of the innate and/or adaptive immune system's positive-feedback loops are important in avoiding death, promoting a cure, and in suppressing subsequent autoimmune behavior. Stochastic viral replication at the edge of instability can lead to cure or non-cure behaviors, depending on chance. We show that feedback-loop visualizations and time-dependent small-signal eigen-circuit analyses of nonlinear dynamics provide insight into identifying a reduced set of parameters that determine stability, phase transitions, and final behavior.