Dose-dependent interaction of parasites with tiers of host defence generates "wormholes" that prolong infection at intermediate inoculum sizes

Immune responses are induced by parasite exposure and can in turn reduce parasite burden. Despite such apparently simple rules of engagement, key drivers of within-host dynamics, including dose-dependence of defence and infection duration, have proven difficult to predict. Here, we model how varied inoculating doses interact with host defences. Defence is multi-tiered, with 3 tiers invoked for all animals: barrier, innate, and adaptive. We model how these tiers interact with replicating and non-replicating parasites across six orders of magnitude of dose. We find that, in general, intermediate parasite doses generate infections of longest duration because they are sufficient in number to breach barrier defences, but insufficient to strongly induce subsequent tiers of defence. Deviation from the hypothesis of independent action, which postulates that each parasite has an independent probability of establishing infection, may therefore be widespread. Most interestingly, our model predicts local maxima of duration at two doses - one for each tier transition. While empirical evidence is consistent with nonlinear dose-dependencies, the profiles with multiple turning points that we predict will require finer-scale dose experiments than are usually undertaken. Our results help explain varied infection duration among differentially-exposed hosts and elucidate evolutionary pressures that shape both virulence and defence.