Ayres and Schneider's latest work [10] is an analysis of the resistance and tolerance phenotypes of flies with a single mutation in CG3066, a gene encoding a protease active in the melanisation cascade, an innate immunity pathway in invertebrates.
By challenging wild-type and CG3066-defective flies with one of a panel of seven bacterial species, they revealed that this protease can be viewed as a tolerance gene, a resistance gene, or neither, depending on the pathogen involved.
Thus, with some bacterial species, the mutant flies were resistance-defective, dying faster of overwhelming bacteria.
With other species, the same mutation enhanced resistance, with the flies harbouring fewer pathogens and being less likely to die. With two other bacterial species, fly lifespan was unaffected, but for one, the mutant line had lower burdens (resistance-enhanced, tolerance-defective), and for the other, the mutant line had more bacteria (resistance-defective, tolerance-enhanced). In an earlier study [13,14], these same authors reported that mutants in the fly Tumour Necrosis Factor–related molecule “eiger,” when challenged with one bacterial species, lived longer with similar pathogen titres (tolerance-enhanced), and yet when challenged with another species, died faster with reduced titres (resistance-enhanced, tolerance-defective).
Thus, ironically, the first evidence of tolerance genes in flies shows that it does not make sense to talk of “resistance” or “tolerance” genes at all: one gene can be involved in tolerance and resistance, depending on the pathogen.