Immunology’s intolerance to disease tolerance
There is an ancient, theoretical and practical concept in plant ecology that proposes that infected hosts may differ in their ability to reduce the pathogen load (called resistance) and the amount they suffer in response to varying pathogen loads (called disease tolerance).
Tolerance to disease is most clearly observed in cases where different responses to a pathogen save or kill the host, but do not change the load of pathogens. Looking back in 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 debilitating disease which usually results in death. However, an alteration in insulin signaling prolonged survival without affecting the pathogen load. Like many tolerance mechanisms, this did not involve a physiological mechanism that we normally think of as part of the âimmune systemâ, although it is essential for surviving infection.
In 2007, a study by Pamplona et al. reported that heme oxygenase, the enzyme that metabolizes heme to bilirubin, may improve survival in mice with cerebral malaria without affecting parasite load. Again, heme oxygenase was not a typical immunologic effector, but it was essential for survival.
At the time, there was no comprehensive theoretical way to describe disease tolerance in animals. Raberg et al. (2007), in an elegant article that makes many say âI would have liked to think about it! Imported the idea of ââdisease tolerance from plant ecology and applied it to animals. In their study, the authors concluded that different strains of mice, known for their different responses to rodent malaria, could be described as different in terms of tolerance to the disease. This was an important insight as it opened the door to the application of decades of theory and practice from plant science to animal biology.
Around the same time, Ayres et al. (2008) showed that an approximately equal number of resistance and tolerance mutations can be found in Drosophila when screening for factors affecting their survival to infections. Oddly enough, genetic tests for fly immunity had been going on for about 10 years and no disease tolerance effects had been reported, which was probably due to the fact that the first tests looked for changes in immune effectors. but not the survival of the host. The study by Ayres et al. is important because it suggests that it should be easy to find tolerance effects if we take the trouble to look for them.
“It opened the door to the application of decades of theory and practice, from plant science to animal biology”
At the start of the COVID-19 pandemic, we were faced with a pathogen for which we had no effective antiviral treatment and no vaccine. Our only hope was to promote disease tolerance to save lives, and we did; oxygen therapy and anti-inflammatory drugs are tolerance treatments. Given its obvious importance, I had hoped the idea of ââdisease tolerance would gain traction, but it met with resistance. Part of the problem is its name, but we are already dealing with many types of tolerance in immunity – one more shouldn’t be a problem. The most important obstacle might be that understanding tolerance requires studying the entire physiological response of a body, not just isolated immune cells; Perhaps the time has come to study the function of the organism in parallel with biological mechanisms.
Dionne, M. et al. Akt and FOXO deregulation contributes to infection-induced wasting in Drosophila. Court. Biol. 16, 1977-1985 (2006)
Pamplona, ââA. 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. Unraveling genetic variation for resistance and tolerance to infectious diseases in animals. Science 318, 812-814 (2007)
Ayres, JS et al. Identification of Drosophila mutants altering the defense and endurance of Listeria monocytogenes infection. Genetic 178, 1807-1815 (2008)
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Schneider, DS Immunology’s Intolerance to Disease Tolerance.
Nat Rev Immunol 21, 624-625 (2021). https://doi.org/10.1038/s41577-021-00619-7