Tolerance of Infections

Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
Annual Review of Immunology (Impact Factor: 39.33). 03/2011; 30(1):271-94. DOI: 10.1146/annurev-immunol-020711-075030
Source: PubMed


A host has two methods to defend against pathogens: It can clear the pathogens or reduce their impact on health in other ways. The first, resistance, is well studied. Study of the second, which ecologists call tolerance, is in its infancy. Tolerance measures the dose response curve of a host's health in reaction to a pathogen and can be studied in a simple quantitative manner. Such studies hold promise because they point to methods of treating infections that put evolutionary pressures on microbes different from antibiotics and vaccines. Studies of tolerance will provide an improved foundation to describe our interactions with all microbes: pathogenic, commensal, and mutualistic. One obvious mechanism affecting tolerance is the intensity of an immune response; an overly exuberant immune response can cause collateral damage through immune effectors and because of the energy allocated away from other physiological functions. There are potentially many other tolerance mechanisms, and here we systematically describe tolerance using a variety of animal systems.

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    • "Whilst between-strain variation in nematode resistance has been previously described (Behnke et al., 2006), there is no evidence of description of variation in tolerance. Resistance describes the ability of the host to clear pathogens, whereas tolerance describes the ability to reduce the health or fitness impact of a given infection intensity (Ayres and Schneider, 2012; Raberg, 2014). Characterising the tolerance of mouse strains that differ in their resistance to H. bakeri infection will facilitate the selection of the most appropriate mouse strain to model nematodiasis in human and livestock hosts. "
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    ABSTRACT: The relationship between the manifestations of tolerance (a host’s ability to reduce the impact of a given level of pathogens) and resistance (a host’s ability to clear pathogens) has been assumed to be an antagonistic one. Here we tested the hypothesis that mice from strains more resistant to intestinal nematodes will experience reduced tolerance compared with less resistant mice. Three inbred strains of mice were used: C57BL/6 mice have been characterised as susceptible, whereas BALB/c and NIH mice have been characterised as resistant to Heligmosomoides bakeri infection. Mice of each strain were either parasitised with a single dose of 250 L3 H. bakeri (n = 10) in water or were sham-infected with water (n = 10). Body weight, food intake and worm egg output were recorded regularly throughout the experiment. Forty-two days p.i. mice were euthanised and organ weights, eggs in colon and worm counts were determined. C57BL/6 mice showed significantly greater worm egg output (P < 0.001), eggs in colon (P < 0.05) and female worm fecundity (P < 0.05) compared with NIH and BALB/c mice. Parasitised BALB/c mice grew more whilst parasitised C57BL/6 mice grew less than their sham-infected counterparts during the first 2 weeks post-challenge (P = 0.05). Parasitism significantly increased liver, spleen, small intestine and caecum weights (P < 0.001) but reduced carcass weight (P < 0.01). Average daily weight gain and worm numbers were positively correlated in NIH mice (P = 0.05); however, the relationship was reversed when carcass weight was used as a measure for tolerance. BALB/c mice did not appear to suffer from the consequences of parasitism, with carcass weight similar in all animals. Our hypothesis that strains more resistant to the H. bakeri infection are less tolerant compared with less resistant strains is rejected, as the two resistant strains showed variable tolerance. Thus, tolerance and resistance to an intestinal nematode infection are not always mutually exclusive.
    International Journal for Parasitology 02/2015; 45(4). DOI:10.1016/j.ijpara.2014.12.005 · 3.87 Impact Factor
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    • "The salutary effects of this defense strategy are illustrated by the protective effect of vaccination against a wide range of infectious diseases. There is, however, another host defense strategy that limits disease severity irrespectively of pathogen burden, i.e., disease tolerance (Ayres and Schneider, 2012; Medzhitov et al., 2012; Schneider and Ayres, 2008). Revealed originally in plants and thereafter in flies, disease tolerance also operates in mammals, as demonstrated for Plasmodium (Rå berg et al., 2007; Seixas et al., 2009) and polymicrobial (Larsen et al., 2010) infection in mice. "
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    ABSTRACT: Immune-driven resistance mechanisms are the prevailing host defense strategy against infection. By contrast, disease tolerance mechanisms limit disease severity by preventing tissue damage or ameliorating tissue function without interfering with pathogen load. We propose here that tissue damage control underlies many of the protective effects of disease tolerance. We explore the mechanisms of cellular adaptation that underlie tissue damage control in response to infection as well as sterile inflammation, integrating both stress and damage responses. Finally, we discuss the potential impact of targeting these mechanisms in the treatment of disease.
    Trends in Immunology 10/2014; 35(10). DOI:10.1016/ · 10.40 Impact Factor
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    • "It has been well documented that resistance and tolerance are important factors to consider when analyzing the effects of pathogens on infected hosts [ 39 , 41 – 45 ] . Resistance and tolerance are context - dependent and can be measured by various param - eters that include pathogen load and health of the host ( see review by Ayres and Schneider , 2012 ) . For example , it has been "
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    ABSTRACT: Drosophila melanogaster flies mount an impressive immune response to a variety of pathogens with an efficient system comprised of both humoral and cellular responses. The fat body is the main producer of the anti-microbial peptides (AMPs) with anti-pathogen activity. During bacterial infection, an array of secreted peptidases, proteases and other enzymes are involved in the dissolution of debris generated by pathogen clearance. Although pathogen destruction should result in the release a large amount of nucleic acids, the mechanisms for its removal is still not known. In this report, we present the characterization of a nuclease gene that is induced not only by bacterial infection but also by oxidative stress. Expression of the identified protein has revealed that it encodes a potent nuclease that has been named Stress Induced DNase (SID). SID belongs to a family of evolutionarily conserved cation-dependent nucleases that degrade both single and double-stranded nucleic acids. Down-regulation of sid expression via RNA interference lead to significant reduction of fly viability after bacterial infection and oxidative stress. Our results indicate that SID protects flies from the toxic effects of excess DNA/RNA released by pathogen destruction and from oxidative damage.
    PLoS ONE 08/2014; DOI:10.1371/journal.pone.0103564 · 3.23 Impact Factor
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