Dose-dependent interaction of parasites with tiers of host defense predicts "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 defense and infection duration, have proven difficult to predict. Here, we model how varied inoculating doses interact with multi-tiered host defenses at a site of inoculation, by confronting barrier, innate, and adaptive tiers with replicating and non-replicating parasites across multiple 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 defenses, but insufficient to strongly induce subsequent tiers of defense. These doses reveal "wormholes" in defense from which parasites might profit: Deviation from the hypothesis of independent action, which postulates that each parasite has an independent probability of establishing infection, may therefore be widespread. Interestingly, our model predicts local maxima of duration at two doses-one for each tier transition. While some empirical evidence is consistent with nonlinear dose-dependencies, testing the predicted dynamics will require finer-scale dose variation than experiments usually incorporate. Our results help explain varied infection establishment and duration among differentially-exposed hosts and elucidate evolutionary pressures that shape both virulence and defense.