Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases

Abstract

A host can evolve two types of defence mechanism to increase its fitness when challenged with a pathogen: resistance and tolerance. Immunology is a well-defined field in which the mechanisms behind resistance to infection are dissected. By contrast, the mechanisms behind the ability to tolerate infections are studied in a less methodical manner. In this Opinion, we provide evidence that animals have specific tolerance mechanisms and discuss their potential clinical impact. It is important to distinguish between these two defence mechanisms because they have different pathological and epidemiological effects. An increased understanding of tolerance to pathogen infection could lead to more efficient treatments for infectious diseases and a better description of host-pathogen interactions.

Figure 1. Definitions and implications of resistance and tolerance

Resistance, which is a measurement of the ability of an individual host to limit pathogen growth, can be interpolated from these graphs as the inverse of the mean of the pathogen load. Tolerance, which is a measurement of the ability of an individual host to survive an infection at a given pathogen load, is the slope of the curve relating host health to pathogen load. Examples of different reaction norms adapted from Raberg et al.

Figure 2. Correlation between resistance and tolerance

This figure shows a core set of mechanisms that are involved in both resistance and tolerance in the fruit fly. As the figure moves into its outer rings, we predict that the tolerance mechanisms will have smaller and smaller effects on resistance. For example, alterations of immune effectors and receptors, on the left, will have strong effects on both tolerance and resistance. Immune modifiers in the center will have an intermediate effect. Outlying tolerance mechanisms will still certainly have effects on resistance but the effects might be smaller than those that modify resistance mechanisms.

Figure 3. Applications of resistance and tolerance to medical treatment

We propose that every patient has an tolerance curve describing the health of that patient in relation to their pathogen load. Health can be increased by reducing pathogen load or by drastically altering the shape of the tolerance curve.