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Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases

Abstract

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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Figure 1: Definitions and implications of resistance and tolerance.
Figure 2: Mechanisms of tolerance.
Figure 3: Applications of resistance and tolerance to medical treatment.

References

  1. Schafer, J. Tolerance to plant disease. Annu. Rev. Phytopathol. 9, 235–252 (1971).

    Article  Google Scholar 

  2. Clarke, D. Tolerance of parasites and disease in plants and its significance in host–parasite interactions. Adv. Plant Pathol. 5, 161–197 (1986).

    Google Scholar 

  3. Stowe, K., Marquis, R., Hochwender, C. & Simms, E. L. The evolutionary ecology of tolerance to consumer damage. Annu. Rev. Ecol. Syst. 31, 565–595 (2000).

    Article  Google Scholar 

  4. Kover, P. X. & Schaal, B. A. Genetic variation for disease resistance and tolerance among Arabidopsis thaliana accessions. Proc. Natl Acad. Sci. USA 99, 11270–11274 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Schwachtje, J. et al. SNF1-related kinases allow plants to tolerate herbivory by allocating carbon to roots. Proc. Natl Acad. Sci. USA 103, 12935–12940 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Simms, E. Defining tolerance as a norm of reaction. Evol. Ecol. 14, 563–570 (2000).

    Article  Google Scholar 

  7. Simms, E. L. & Triplett, J. Costs and benefits of plant responses to disease: resistance and tolerance. Evolution 48, 1973–1985 (1994).

    Article  PubMed  Google Scholar 

  8. Tiffin, P. & Inouye, B. D. Measuring tolerance to herbivory: accuracy and precision of estimates made using natural versus imposed damage. Evolution 54, 1024–1029 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Lambeth, J. D., Kawahara, T. & Diebold, B. Regulation of Nox and Dox enzymatic activity and expression. Free Radic. Biol. Med. 43, 319–331 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lambeth, J. D. Nox enzymes, ROS and chronic disease: an example of antagonistic pleiotropy. Free Radic. Biol. Med. 43, 332–347 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lazzaro, B. P. Natural selection on the Drosophila antimicrobial immune system. Curr. Opin. Microbiol. 11, 284–289 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Leulier, F. & Lemaitre, B. Toll-like receptors — taking an evolutionary approach. Nature Rev. Genet. 9, 165–178 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Clark, I. A. How TNF was recognized as a key mechanism of disease. Cytokine Growth Factor Rev. 18, 335–343 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Pamplona, A. et al. Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nature Med. 13, 703–710 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Dionne, M. S., Pham, L. N., Shirasu-Hiza, M. & Schneider, D. S. Akt and FOXO dysregulation contribute to infection-induced wasting in Drosophila. Curr. Biol. 16, 1977–1985 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Natanson, C. et al. Endotoxin and tumor necrosis factor challenges in dogs stimulate the cardiovascular profile of human septic shock. J. Exp. Med. 169, 823–832 (1989).

    Article  CAS  PubMed  Google Scholar 

  17. Reece, J. J., Siracusa, M. C. & Scott, A. L. Innate immune responses to lung-stage helminth infection induce alternatively activated alveolar macrophages. Infect. Immun. 74, 4970–4981 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Loke, P. et al. Alternative activation is an innate response to injury that requires CD4+ T cells to be sustained during chronic infection. J. Immun. 179, 3926–3936 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Aidoo, M. et al. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 359, 1311–1312 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Williams, T. N. et al. Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases. J. Inf. Dis. 192, 178–186 (2005).

    Article  Google Scholar 

  21. Williams, T. N. et al. Both heterozygous and homozygous α+ thalassemias protect against severe and fatal Plasmodium falciparum malaria on the coast of Kenya. Blood 106, 368–371 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Wambua, S. et al. The effect of α+-thalasemia on the incidence of malaria and other diseases in children living in the coast of Kenya. PLoS Med. 3, e158 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Guindo, A., Fairhurst, R. M., Doumbo, O. K., Wellems, T. E. & Diallo, D. A. X-linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria. PLoS Med. 4, e66 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lambrechts, L., Halbert, J., Durand, P., Gouagna, L. C. & Koella, J. C. Host genotype by parasite genotype interactions underlying the resistance of anopheline mosquitos to Plasmodium falciparum. Malar. J. 4, 3 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lazzaro, B. P., Sceurman, B. K. & Clark, A. G. Genetic basis of natural variation in D. melanogaster antibacterial immunity. Science 303, 1873–1876 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Cotter, S. C., Kruuk, L. E. B. & Wilson, K. Cost of resistance: genetic correlations and potential trade-offs in an insect immune system. J. Evol. Biol. 17, 421–429 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Lemaitre, B., Nicolas, E., Michaut, L., Reichart, J. M. & Hoffmann, J. A. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potential antifungal response in Drosophila adults. Cell 86, 973–983 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Ip, Y. T. et al. Dif, a dorsal-related gene that mediates an immune response in Drosophila. Cell 75, 753–763 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Wu, L. P. & Anderson, K. V. Regulated nuclear import of Rel proteins in the Drosophila immune response. Nature 392, 93–97 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Meng, X., Khanuja, B. S. & Ip, Y. T. Toll receptor-mediated Drosophila immune response requires Dif, an NF-κB factor. Genes Dev. 13, 792–797 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tauszig-Delamasure, S., Bilak, H., Capovilla, M., Hoffmann, J. A. & Imler, J. Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections. Nature Immunol. 3, 91–97 (2002).

    Article  CAS  Google Scholar 

  32. Levashina, E. A. et al. Constitutive activation of Toll-mediated antifungal defense in serpin-deficient Drosophila. Science 285, 1917–1919 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Weber, A. N. et al. Binding of the Drosophila cytokine Spatzle to Toll is direct and establishes signaling. Nature Immunol. 4, 794–800 (2003).

    Article  CAS  Google Scholar 

  34. Lemaitre, B. A recessive mutation, immune deficiency (imd), defines two distinct pathways in the Drosophila host defense. Proc. Natl Acad. Sci. USA 92, 9465–9469 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Leulier, F., Rodriguez, A., Khush, R. S., Abrams, J. M. & Lemaitre, B. The Drosophila caspase Dredd is required to resist Gram-negative bacterial infections. EMBO Rep. 1, 353–358 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rutschmann, S. et al. Role of Drosophila IKKγ in a Toll-independent antibacterial immune response. Nature Immunol. 1, 342–347 (2000).

    Article  CAS  Google Scholar 

  37. Hedengren, M. et al. Relish, a central factor in the control of humoral, but not cellular immunity in Drosophila. Mol. Cell 4, 827–837 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Naitza, S. et al. The Drosophila immune defense against Gram-negative infection requires the death protein Dfadd. Immunity 17, 575–581 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Gottar, M. et al. The Drosophila immune response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein. Nature 416, 640–644 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Lau, G. W. et al. The Drosophila melanogaster Toll pathway participates in resistance to infection by the Gram-negative human pathogen Pseudomonas aeruginosa. Infect. Immun. 71, 4059–4066 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Corby-Harris, V., Habel, K. E., Ali, F. G. & Promislow, D. E. Alternative measures of response to Pseudomonas aeruginosa infection in Drosophila melanogaster. J. Evol. Biol. 20, 526–533 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Råberg, L., Sim, D. & Read, A. F. Disentangling genetic variation for resistance and tolerance to infectious diseases in animals. Science 318, 812–814 (2007).

    Article  PubMed  Google Scholar 

  43. Ma, Y. et al. Distinct characteristics of resistance to Borrelia burgdorferi-induced arthritis in C57BL/56N mice. Infect. Immun. 66, 161–168 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kane, G. C. et al. Gene knockout of the KCNJ8-encoded Kir6.1 KATP channel imparts fatal susceptibility to endotoxemia. FASEB J. 20, 2271–2280 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Croker, B. et al. ATP-sensitive potassium channels mediate survival during infection in mammals and insects. Nature Genet. 39, 1453–1460 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Beeson, P. B. Tolerance to bacterial pyrogens I: factors influencing its development. J. Exp. Med. 86, 29–38 (1947).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Beeson, P. B. Tolerance to bacterial pyrogens II: role of the reticulo-endothelial system. J. Exp. Med. 86, 39–44 (1947).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. West, M. A. & Heagy, W. Endotoxin tolerance: a review. Crit. Care Med. 30, S64–S73 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Cavaillon, J. M. & Adib-Conquy, M. Bench to bedside: endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit. Care 10, 1–8 (2006).

    Article  Google Scholar 

  50. Medvedev, A. E., Kopydlowski, K. M. & Vogel, S. N. Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: dysregulation of cytokine, chemokine and toll-like receptor 2 and 4 gene expression. J. Immunol. 164, 5564–5574 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Medvedev, A. E., Lentschat, A., Wahl, L. M., Golenbock, D. T. & Vogel, S. N. Dysregulation of LPS-induced Toll-like receptor 4–MyD88 complex formation and IL-1 receptor associated kinase 1 activation in endotoxin-tolerant cells. J. Immunol. 169, 5209–5216 (2002).

    Article  PubMed  Google Scholar 

  52. Dobrovolskaia, M. A. et al. Induction of in vitro reprogramming by Toll-like receptor TLR2 and TLR4 agonists in murine macrophages: effects of TLR “homotolerance” versus “heterotolerance” on NF-κB signaling pathway components. J. Immunol. 170, 508–519 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Sinton, J. A. Immunity or tolerance in malarial infections. Proc. R. Soc. Med. 31, 1298–1302 (1938).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Gatton, M. L. & Cheng, Q. Evaluation of the pyrogenic threshold for the Plasmodium falciparum malaria in naïve individuals. Am. J. Trop. Med. Hyg. 66, 467–473 (2002).

    Article  PubMed  Google Scholar 

  56. Boutlis, C. S., Yeo, T. W. & Anstey, N. M. Malaria tolerance — for whom the cell tolls? Trends Parasitol. 22, 371–377 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ayres, J. S., Freitag, N. & Schneider, D. S. Identification of Drosophila mutants altering defense and endurance of to Listeria monocytogenes infection. Genetics 178, 1807–1815 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Franklin, B. S. et al. MyD88-dependent activation of dendritic cells and CD4+ T lymphocytes mediates symptoms but is not required for the immunological control of parasites during rodent malaria. Microbes Infect. 9, 881–890 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Li, C., Corraliza, I. & Langhorne, J. A defect in interleukin-10 leads to enhanced malaria disease in Plasmodium chabaudi chabaudi infection in mice. Infect. Immun. 67, 4435–4442 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Ramsden, S., Cheung, Y. & Seroude, L. Functional analysis of the Drosophila immune response during aging. Aging Cell 7, 225–236 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Schneider, D. S. et al. Drosophila eiger mutants are sensitive to extracellular pathogens. PLoS Pathog. 3, e41 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Brandt, S. M. et al. Secreted bacterial effectors and host-produced Eiger/TNF drive death in a Salmonella-infected fruit fly. PLoS Biol. 2, e418 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Prasad, K. & Singh, M. B. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst. Rev. 1, CD002244 (2008).

    Google Scholar 

  64. Rausher, M. D. Co-evolution and plant resistance to natural enemies. Nature 411, 857–863 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Woolhouse, M. E. J., Webster, J. P., Domingo, E., Charlesworth, B. & Levin, B. Biological and biomedical implications of the co-evolution of pathogens and their hosts. Nature Genet. 32, 569–577 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Boots, M. Fight or learn to live with the consequences. Trends Ecol. Evol. 23, 248–250 (2008).

    Article  PubMed  Google Scholar 

  67. Miller, M. R., White, A. & Boots, M. The evolution of parasites in response to tolerance in their hosts: the good, the bad and the apparent commensalism. Evolution 60, 945–956 (2006).

    Article  PubMed  Google Scholar 

  68. Roy, B. A. & Kirchner, J. W. Evolutionary dynamics of pathogen resistance and tolerance. Evolution 54, 51–63 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Rosenthal, J. P. & Kotanen, P. M. Terrestrial plant tolerance to herbivory. Trends Ecol. Evol. 9, 145–148 (1994).

    Article  CAS  PubMed  Google Scholar 

  70. Strauss, S. & Agrawal, A. The ecology and evolution of tolerance to herbivory. Trends Ecol. Evol. 14, 179–185 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Tiffin, P. Are tolerance, avoidance and antibiosis evolutionarily and ecologically equivalent responses of plants to herbivores? Am. Nat. 155, 128–138 (2000).

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants AI060164, AI053080 and AI055651 from the National Institutes of Health, USA.

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Correspondence to David S. Schneider.

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DATABASES

OMIM

α-thalassaemia

glucose-6-phosphate dehydrogenase (G6PDH) deficiency

sickle-cell anaemia

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Schneider, D., Ayres, J. Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases. Nat Rev Immunol 8, 889–895 (2008). https://doi.org/10.1038/nri2432

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