Variation in infection duration is a ubiquitous property of host-parasite interaction. Even in lab settings, where aspects of the interaction can be tightly controlled (e.g., inbred hosts, raised in constant temperatures on a fixed diet, are inoculated with identical doses of genetically identical parasites), hosts will still vary in duration, with some individuals never becoming infected, some clearing infection in a matter of days, some in weeks, and some never clearing the infection at all. Of factors known to influence duration, infectious dose is perhaps the best studied. Vexingly, however, the influence of dose on duration is not straightforward: in some contexts, increasing dose increases duration, whereas in others it decreases it. From a theoretical point of view, variation in dose amounts to a change in the initial conditions of the within-host immune-parasite interaction. Current theory for studying within-host interactions, however, treats infection duration as an assumption rather than an outcome of the interaction – that is, the only way to vary infection duration is by changing the structure of the model itself. Theory has thus been unable to further our understanding of the drivers of infection duration variation in response to dose or its higher-level (epidemiological and evolutionary) consequences.
Results/Conclusions
Here I show that this limitation is primarily because current within-host models are inspired by predator-prey theory, and thus lack important positive and negative feedback mechanisms that are intrinsic to the immune-parasite interaction. For example, parasites often manipulate either the host immune response or access to within-host resources, generating positive density-dependent feedback; on the other hand, the immune system uses positive feedback loops (e.g., between cytokines and T-cells) to ramp up the immune response and negative feedback loops (e.g., activation-induced cell death) to regulate itself. Incorporation of these feedback mechanisms generates Allee effects in immune and parasite dynamics that drive bistability between acute (short-term) and chronic (long-term) infections. Whether parasite-mediated or immune-mediated feedbacks are operating determines whether increasing dose is likely to lead to a longer or shorter infection. Moreover, I show that when both mechanisms are operating, factors like host diet and where the parasite lives within the body can determine which feedbacks predominate to drive variation in infection duration. Scaling up these simple within-host models to the population level will help to predict variation in epidemiological dynamics across environments.