Evolving Mechanisms of Disease Tolerance

Historically, immunologists considered host defense as the ability to detect and destroy pathogens. However, protection may also be afforded by tolerating the presence of the pathogen while controlling tissue damage caused by pathogen-derived virulence factors or the immune response. Evidence for this alternative defense strategy, known as disease tolerance, was initially described in plants and insects, but has only recently been demonstrated in mammals.

Disease resistance is operationally defined as a decrease in pathogen burden via either neutralization or killing with limited immunopathologic sequelae. By contrast, disease tolerance is the ability to maintain host fitness without affecting pathogen burden. While the mechanisms by which resistance occurs have been investigated in detail, the mechanisms of disease tolerance are only beginning to emerge. Importantly, these host defense strategies are not necessarily mutually exclusive but are employed to varying degrees depending on the pathogen and the site of infection. However, one of the costs of disease tolerance is pathogen persistence. In fact, the ability of diverse classes of microorganisms to actively manipulate or evade the host immune response without causing overt pathology indicates that both host and microbe have evolved strategies that promote a state of equilibrium for their mutual benefit.

By exploring the mechanisms of disease tolerance across the kingdoms of life, we propose to examine the mechanisms by which disease tolerance pathways have evolved and engaged to maintain host fitness but, as a consequence, permit pathogen survival.