Article

Disease Tolerance as a Defense Strategy

Howard Hughes Medical Institute, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Science (Impact Factor: 33.61). 02/2012; 335(6071):936-41. DOI: 10.1126/science.1214935
Source: PubMed

ABSTRACT

The immune system protects from infections primarily by detecting and eliminating the invading pathogens; however, the host
organism can also protect itself from infectious diseases by reducing the negative impact of infections on host fitness. This
ability to tolerate a pathogen’s presence is a distinct host defense strategy, which has been largely overlooked in animal
and human studies. Introduction of the notion of “disease tolerance” into the conceptual tool kit of immunology will expand
our understanding of infectious diseases and host pathogen interactions. Analysis of disease tolerance mechanisms should provide
new approaches for the treatment of infections and other diseases.

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Available from: David Schneider, Jun 28, 2015
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    • "The immune response in API is often described as disease resistance, which is associated with a reduction in pathogen burden; therefore, this protective mechanism reduces tissue damage and immunopathology related to malarial infection (Medzhitov et al. 2012). In contrast, some individuals can control disease manifestation despite not being able to reduce levels of parasitaemia; this phenomenon is described as disease tolerance (Medzhitov et al. 2012). Immunity to malaria does not necessarily prevent infection; however, it does limit parasite density and symptoms (Tran et al. 2013). "
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    • "It remains to be determined whether there is a benefit to the host or whether, alternatively, the pathogen-induced oxidative stress represents simply a metabolic by-product of the IFN-I driven response. We speculate that this process might bear relevance for the metabolic rewiring of the cell, whereby the IFN-I driven transient changes in the redox status contribute to the rapidly changing bioenergetic and signaling demands as part of the antiviral state and/or of mechanisms of disease tolerance (Everts et al., 2014; Medzhitov et al., 2012; Pantel et al., 2014; Schieber and Chandel, 2014; Weinberg et al., 2015). The molecular understanding of such crosstalk between metabolic and inflammatory processes might also contribute to a better understanding of the mechanism(s) of action and side effects of IFN-I therapies in non-infectious diseases like multiple sclerosis and cancer (Reder and Feng, 2014; Sistigu et al., 2014). "
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    ABSTRACT: Tissue damage caused by viral hepatitis is a major cause of morbidity and mortality worldwide. Using a mouse model of viral hepatitis, we identified virus-induced early transcriptional changes in the redox pathways in the liver, including downregulation of superoxide dismutase 1 (Sod1). Sod1(-/-) mice exhibited increased inflammation and aggravated liver damage upon viral infection, which was independent of T and NK cells and could be ameliorated by antioxidant treatment. Type I interferon (IFN-I) led to a downregulation of Sod1 and caused oxidative liver damage in Sod1(-/-) and wild-type mice. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against virus-induced liver damage. These results delineate IFN-I mediated oxidative stress as a key mediator of virus-induced liver damage and describe a mechanism of innate-immunity-driven pathology, linking IFN-I signaling with antioxidant host defense and infection-associated tissue damage. VIDEO ABSTRACT.
    Full-text · Article · Nov 2015 · Immunity
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    • "Tolerance is a concept routinely used by phytopathologists that has been recently adapted to animal infections (Raberg et al., 2007) and refers to individuals that withstand the infection, paying small or no costs at all (Schneider and Ayres, 2008). Even though immunological tolerance and tolerance of the infection are not strictly synonymous terms, tolerance of the infection often involves the activation of immunological effectors that prevent immunopathology (Medzhitov et al., 2012). We therefore provided a different immune environment to the parasite, and exposed the hosts to different environmental risks using different infective doses that simulate a more or less safe environment. "
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    ABSTRACT: The outcome of the encounter between a host and a parasite depends on the synergistic effects of the genetics of the two partners and the environment (sensulato) where the interaction takes place. Reaction norms can depict how host and parasite traits vary across environmental ranges for different genotypes. Here, we performed a large scale experiment where three strains of laboratory mice (SJL, BALB/c and CBA) were infected with four doses of the intestinal nematode Heligmosomoides polygyrus. An increasing infective dose can be considered as a proxy for the environment-dependent risk incontracting the infection. We looked at the fitness traits of hosts and parasites, and assessed the underlying immunological functions likely to affect the observed pattern of resistance/susceptibility/tolerance. We found that the infective dose had a strong effect on both host fitness and parasite performance. Interestingly, for most traits, host genotypes did not rank consistently across the increasing infective doses and according to the expected pattern of strain-specific resistance/susceptibility/tolerance. Analyses of cytokine production allowed better understanding of the mechanistic basis underlying variations in fitness-linked traits. The infective dose affected the shape of the reaction norms of the cytokines IL-4, IL-10 and IL-6. Dose-dependent variation in cytokine production explained, moreover, the strain-specific pattern of infection cost, host resistance and parasite performance. As long as the infective dose increased, there was a marked shift towards a pro-inflammatory status in the SJL strain of mice that was positively correlated with cost of the infection and parasite performance. Overall, our study strongly suggests that the notion of host resistance is labile and depends on the environmental conditions where the interaction takes place. Moreover, integrating information on fitness-linked traits and the underlying mechanisms seems essential for a better understanding of host and parasite adaptations across variable environments.
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