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.
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"To study infection-induced pathogenesis, we need reliable methods of quantifying its measurement. One method that has been used to study the pathogenesis of infectious diseases in populations is to measure disease tolerance . Disease tolerance is a dose response curve that summarizes the entire infection by plotting summary health and microbe measurements for each infected individual. For example, mouse strains can be differentiated with respect to their disease tolerance to malaria by plotting graphs correlating the lowest red blood cell count (minimum health) by maximum parasite density and demonstrating that the curves have different slopes . "
[Show abstract][Hide abstract]ABSTRACT: Infected hosts differ in their responses to pathogens; some hosts are resilient and recover their original health, whereas others follow a divergent path and die. To quantitate these differences, we propose mapping the routes infected individuals take through "disease space." We find that when plotting physiological parameters against each other, many pairs have hysteretic relationships that identify the current location of the host and predict the future route of the infection. These maps can readily be constructed from experimental longitudinal data, and we provide two methods to generate the maps from the cross-sectional data that is commonly gathered in field trials. We hypothesize that resilient hosts tend to take small loops through disease space, whereas nonresilient individuals take large loops. We support this hypothesis with experimental data in mice infected with Plasmodium chabaudi, finding that dying mice trace a large arc in red blood cells (RBCs) by reticulocyte space as compared to surviving mice. We find that human malaria patients who are heterozygous for sickle cell hemoglobin occupy a small area of RBCs by reticulocyte space, suggesting this approach can be used to distinguish resilience in human populations. This technique should be broadly useful in describing the in-host dynamics of infections in both model hosts and patients at both population and individual levels.
"Since there are not universally agreed upon definitions for many of the words we use to describe the immune response and health, we start by defining the following terms: vigor, resistance , resilience, and tolerance. " Vigor " is the health of an uninfected individual, and " resistance " describes the host's ability to limit microbe load . We use " resilience " to describe the ability of infected hosts to return to their original healthy condition, much in the same way the word is used to describe the way a perturbed ecological system returns to its origin [7,8]. "
[Show abstract][Hide abstract]ABSTRACT: The study of infectious disease has been aided by model organisms, which have helped to elucidate molecular mechanisms and contributed to the development of new treatments; however, the lack of a conceptual framework for unifying findings across models, combined with host variability, has impeded progress and translation. Here, we fill this gap with a simple graphical and mathematical framework to study disease tolerance, the dose response curve relating health to microbe load; this approach helped uncover parameters that were previously overlooked. Using a model experimental system in which we challenged Drosophila melanogaster with the pathogen Listeria monocytogenes, we tested this framework, finding that microbe growth, the immune response, and disease tolerance were all well represented by sigmoid models. As we altered the system by varying host or pathogen genetics, disease tolerance varied, as we would expect if it was indeed governed by parameters controlling the sensitivity of the system (the number of bacteria required to trigger a response) and maximal effect size according to a logistic equation. Though either the pathogen or host immune response or both together could theoretically be the proximal cause of pathology that killed the flies, we found that the pathogen, but not the immune response, drove damage in this model. With this new understanding of the circuitry controlling disease tolerance, we can now propose better ways of choosing, combining, and developing treatments.
"Host immune-mediation: Microbes can elicit a host immune response to which the parasite is not resistant [40,42]. Host tolerance-mediation: Microbes can increase the fitness of their host during infection without reducing the fitness of the parasite by enhancing host tolerance (e.g., via tissue damage prevention and/or repair) [43,44]. "