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  • Review Article
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Disease tolerance and immunity in host protection against infection

Nature Reviews Immunology volume 17, pages 83–96 (2017)Cite this article

Subjects

Key Points

  • Disease tolerance is an evolutionarily conserved defence strategy against infection that does not exert a direct negative effect on the host pathogen load.

  • Disease tolerance relies on tissue damage control mechanisms.

  • Tissue damage control mechanisms rely on stress and damage responses.

  • Innate and adaptive components of the immune system regulate tissue damage control mechanisms and contribute to the establishment of disease tolerance to infection.

  • Host–commensal microorganism interactions regulate disease tolerance against pathogens.

  • Pharmacological targeting of tissue damage control mechanisms induces disease tolerance to infection.

Abstract

The immune system probably evolved to limit the negative effects exerted by pathogens on host homeostasis. This defence strategy relies on the concerted action of innate and adaptive components of the immune system, which sense and target pathogens for containment, destruction or expulsion. Resistance to infection refers to these immune functions, which reduce the pathogen load of an infected host as the means to preserve homeostasis. Immune-driven resistance to infection is coupled to an additional, and arguably as important, defence strategy that limits the extent of dysfunction imposed on host parenchymal tissues during infection, without exerting a direct negative effect on pathogens. This defence strategy, known as disease tolerance, relies on tissue damage control mechanisms that prevent the deleterious effects of pathogens and that uncouples immune-driven resistance mechanisms from immunopathology and disease. In this Review, we provide a unifying view of resistance and disease tolerance in the framework of immunity to infection.

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Figure 1: Tissue damage control and disease tolerance.
Figure 2: Relative contribution of stress and damage responses to the establishment of disease tolerance to infection.
Figure 3: Immune regulation of tissue damage control.
Figure 4: Pathogen class-specific tissue damage control mechanisms.

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Acknowledgements

The authors thank J. Thompson and F. Brazza for insightful comments and S. Ramos for careful review and editing of the manuscript (Instituto Gulbenkian de Ciência). M.P.S. is supported by Fundação Calouste Gulbenkian, Fundação para a Ciência e Tecnologia (FCT; PTDC/SAU-TOX/116627/2010 and HMSP-ICT/0022/2010) and the European Community 7th Framework program (ERC-2011-AdG 294709-DAMAGECONTROL). L.F.M. is an Fundação para a Ciência e Tecnologia Investigator and is supported by the European Community Horizon 2020 (ERC-2014-CoG 647888-iPROTECTION). L.T. is supported by Fundação Calouste Gulbenkian and Fundação para a Ciência e Tecnologia PTDC/BEX-GMG/3128/2014.

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  1. Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 6, Oeiras, 2780–156, Portugal

    Miguel P. Soares, Luis Teixeira & Luis F. Moita

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  1. Miguel P. Soares
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PowerPoint slides

Glossary

Homeostasis

Maintenance of a stable physiological 'internal' state in multicellular organisms via feedback mechanisms that allow physiological functions to proceed despite variations in the 'external' environment.

Immunopathology

Refers to a breakdown of homeostasis in which immunity functions as the main cause of disease.

Stress

Any variations in the 'external' environment that disrupt the maintenance of a stable physiological environment in which biological processes are allowed to proceed.

Ataxia-telangiectasia mutated kinase

(ATM kinase). A serine and threonine protein kinase that is recruited and activated by DNA double-strand breaks and that has an important role in the activation of DNA damage responses.

Necroptosis

A specific form of programmed cell death mediated via a genetically encoded mechanism involving receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 and the mixed lineage kinase domain-like (MLKL) pseudokinase.

Ferroptosis

Genetically encoded form of programmed cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and by the accumulation of lipid hydroperoxides.

Alarmins

Endogenous molecules released from damaged cells and sensed by receptors of the immune system that alert for tissue dysfunction or damage, associated with disruption of homeostasis.

Nutritional immunity

An evolutionarily conserved resistance mechanism against infection based on the host's ability to withhold nutrients, such as iron, from pathogens.

Anthracycline

A class of red aromatic polyketide drugs derived from Streptomyces spp. bacteria that intercalate into DNA, arresting transcription and cell division, a property widely used therapeutically against cancers.

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Soares, M., Teixeira, L. & Moita, L. Disease tolerance and immunity in host protection against infection. Nat Rev Immunol 17, 83–96 (2017). https://doi.org/10.1038/nri.2016.136

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