A unified model for the coevolution of resistance, tolerance, and virulence.

We present a general host-parasite model that unifies previous theory by investigating the coevolution of virulence, resistance, and tolerance, with respect to multiple physiological, epidemiological, and environmental parameters. Four sets of new predictions emerge. First, compared to virulence coevolving with resistance or tolerance, three-trait coevolution promotes more virulence and less tolerance, and broadens conditions under which pure defenses evolve. Second, the cost and efficiency of virulence and the epidemiological rates are the key factors of virulence coevolving with resistance and tolerance. Maximum virulence evolves for intermediate infection rate, at which coevolved levels of resistance and tolerance are both high. The influence of host and parasite background mortalities is strong on the evolution of defenses and weak on the coevolution of virulence. Third, evolutionary correlations between defenses can switch sign along single-parameter gradients. The evolutionary trade-off between resistance and tolerance may coevolve with virulence that either increases or decreases monotonically, depending on the underlying parameter gradient. Fourth, despite global attractiveness and stability of coevolutionary equilibria, not-so-rare and not-so-small mutations can beget large variation in virulence and defenses around equilibrium, in the form of transient "evolutionary spikes." Implications for evolutionary management of infections are discussed and directions for future research are outlined.