There is an old, theoretical and practical concept from plant ecology that proposes that infected hosts can differ in their ability to reduce pathogen load (called resistance) and the amount they suffer in response to varying pathogen loads (called disease tolerance).
Disease tolerance is most clearly observed in cases where different responses to a pathogen either save or kill the host, but do not alter pathogen load. Looking back through the literature, there are clear examples of this effect in the animal world. For example, a study by Dionne et al. (2006) showed that Mycobacterium marinum infection in Drosophila leads to a wasting disease that usually results in death. However, an alteration in insulin signalling prolonged survival without affecting pathogen load. Like many tolerance mechanisms, this did not involve a physiological mechanism that we normally think of as part of ‘the immune system’, despite being critical for surviving an infection.
In 2007, a study by Pamplona et al. reported that haem oxygenase, the enzyme that metabolizes haem into bilirubin, can enhance survival in mice with cerebral malaria without affecting parasite load. Again, haem oxygenase was not a typical immunological effector, but it was critical for survival.
At the time, there was no overarching theoretical way of describing disease tolerance in animals. Raberg et al. (2007), in an elegant paper that makes many say “I wish I had thought of that!”, imported the idea of disease tolerance from plant ecology and applied it to animals. In their study, the authors concluded that different mouse strains, which were known to differ in their responses to rodent malaria, could be described as differing in terms of their disease tolerance. This was an important insight as it opened the door to applying decades of theory and practice from plant science to animal biology.
Around the same time, Ayres et al. (2008) showed that roughly equal numbers of resistance and tolerance mutations can be found in Drosophila when screening for factors affecting their survival to infections. Oddly, genetic screens for fly immunity had been ongoing for about 10 years and no disease tolerance effects had been reported — which was likely due to the fact that early screens looked for changes in immune effectors but not host survival. The study by Ayres et al. is important because it suggested that it should be easy to find tolerance effects if we bother looking for them.
“it opened the door to applying decades of theory and practice from plant science to animal biology”
At the beginning of the COVID-19 pandemic, we faced a pathogen for which we had no effective antiviral treatments and no vaccine. Our only hope was to promote disease tolerance to save lives, and that is what we did; oxygen treatment and anti-inflammatories are tolerance treatments. Given its obvious importance, I had hoped that the idea of disease tolerance would gain traction, but it has encountered resistance. Part of the problem is its name, yet we already deal with many types of tolerance in immunity – one more should not be a problem. The most important barrier might be that understanding tolerance requires the study of the whole physiological response of a body, not just isolated immune cells; perhaps the time has come to study organismal function in parallel to biological mechanisms.
Dionne, M. et al. Akt and FOXO dysregulation contribute to infection-induced wasting in Drosophila. Curr. Biol. 16, 1977–1985 (2006)
Pamplona, A. et al. Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat. Med. 13, 703–710 (2007)
Raberg, L. et al. Disentangling genetic variation for resistance and tolerance to infectious diseases in animals. Science 318, 812–814 (2007)
Ayres, J. S. et al. Identification of Drosophila mutants altering defense of and endurance to Listeria monocytogenes infection. Genetics 178, 1807–1815 (2008)
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Schneider, D.S. Immunology’s intolerance of disease tolerance. Nat Rev Immunol 21, 624–625 (2021). https://doi.org/10.1038/s41577-021-00619-7