Limiting damage during infection: lessons from infection tolerance for novel therapeutics

Abstract

The distinction between pathogen elimination and damage limitation during infection is beginning to change perspectives on infectious disease control, and has recently led to the development of novel therapies that focus on reducing the illness caused by pathogens (‘‘damage limitation’’)rather than reducing pathogen burdens directly (‘‘pathogen elimination’’). While beneficial at the individual host level, the population consequences of these interventions remain unclear. To address this issue,we present a simple conceptual framework for damage limitation during infection that distinguishes between therapies that are either host-centric (pro-tolerance) or pathogen-centric (anti-virulence). We then draw on recent developments from the evolutionary ecology of disease tolerance to highlight some potential epidemiological and evolutionary responses of pathogens to medical interventions that target the symptoms of infection. Just as pathogens are known to evolve in response to antimicrobial and vaccination therapies, we caution that claims of ‘‘evolution-proof’’ anti-virulence interventions may be premature, and further, that in infections where virulence and transmission are linked, reducing illness without reducing pathogen burden could have non-trivial epidemiological and evolutionary consequences that require careful examination.

Figure 1. The effect of damage limitation mechanisms on the loss of host health during infection.

See Box 1 for further details.

Figure 2. A simple framework for damage limitation.

Damage limitation host mechanisms or drugs may be either host-centric, improving the host's capacity to tolerate infection, or pathogen-centric, targeting pathogen derived molecules that promote virulence. In all cases, damage limitation improves host health without directly eliminating pathogens. See Box 2 for further details.

Figure 3. Two roads to health: elimination and damage limitation.

During infection, pathogen growth causes tissue damage that reduces host health (red circle). Health may be regained through mechanisms that eliminate pathogens (green circle), or instead by mechanisms that reduce the damage caused by pathogens (yellow circle). Such damage limitation mechanisms improve health without reducing pathogen burdens, and therefore could result in hosts being able to tolerate even higher pathogen burdens (scenario 1). Alternatively, reducing the damage caused by infection could also allow the host immune response to eliminate these pathogens (scenario 2). It is currently unclear how host mechanisms of pathogen elimination interact with damage limitation mechanisms.

Figure 4. Epidemiological and evolutionary consequences of damage limitation treatments.

Evolutionarily stable virulence factor production v* (A–C) and prevalence (D–F), plotted against anti-virulence (AV) or pro-tolerance (PT) drug efficacy, r. We plot different levels of how virulence and transmission are related (k). Model details are described in Box 3. Parameter values are as in b1 = 1, b2 = 0.5, d = 1, a = 0.2, σ = 0.1, c = 0.05. Varying the cost of virulence factor production c does not affect the overall trend of the results, although it does affect the magnitude v* and prevalence.