Field of Science

Interesting science - conclusion overstated

In the November 2nd, 3007 issue of Science, there is an article Disentangling Genetic Variation for Resistance and Tolerance to Infectious Diseases in Animals Science 318:5851 p. 812-814.

In plants, there are two ways, evolutionarily speaking, in which a host can respond to a pathogen: resistance and tolerance. In the "normal" case, a pathogen infects a plant grows to a certain level and causes a certain level of disease (which can be death). The thing to note here is that growth and virulence are partially independent. For example, we have ~100,000,000,000 E. coli cells/gram of feces in our gut (lovely isnt it?), so high growth/low virulence. However EHEC (Enterohaemorrhagic E. coli) can get in you and cause a bloody diarrhea and potentially death. The infectious dose of EHEC seems to be in the ballpark of 100,000,000 cells, which we will assume can grow at least a little, so high growth/high virulence. And of course there are examples of low growth/high virulence, and low growth/low virulence. Using that simplistic model what does resistance and tolerance mean. Resistance is essentially preventing a high growth/high virulence organism from growing. If growth is inhibited virulence will be reduced/eliminated. Tolerance, on the other hand, is essentially preventing a high growth/high virulence organism from being virulent without inhibiting growth.

In this paper, the authors start from the premise that genetic variation in plants promotes both resistance and tolerance (true), whereas genetic variation in animals promotes resistance (true). An effect on tolerance by genetic variation has not been analyzed extensively in animals (maybe true/maybe false). Regardless, the authors look to see if they can find evidence of genetic variation promoting tolerance. The authors use a mouse model of malaria as the host-pathogen system. This is a good one, because mice get malaria (as do most, if not all, mammals in areas with Plasmodium species and biting insects. Note: there are unique Plasmodium species (the causative agent of malaria) for each host and unique vectors (the biting insects). Further, there are distinct strains of mice that are like breeds of dogs, and thus have gene sets (alleles) that are different from each other (this is why people from different geographic areas look different, they have different frequencies of certain alleles). The authors then infect these strains of mice with Plasmodium and look to see what happens. Basically what they find is that Plasmodium infection causes a greater reduction in red blood cells (RBCs) in some strains of mice compared to others. Similar results were obtained by analyzing mouse weight loss. Since Plasmodium infects and kills RBCs, causing anemia, leading to weight loss these assays effectively measure virulence. So, some strains get more disease than others, not surprising similar results have been observed for many pathogens in mouse strains (without being published in a journal of Science's caliber). What was interesting is what happens in a given strain if the dose of pathogen varies. If tolerance is an issue adding more or less pathogen (Plasmodium) should have little effect, in other words the effect in RBC reduction should not change much. In a resistant strain, dose is critical, adding more or less pathogen (Plasmodium) will have greater effects. This is what the authors found. A resistant strain C57 (a common mouse background used for making mouse mutants) showed significantly more weight loss at higher doses than lower doses, ok all the strains showed more weight loss at higher doses than lower doses, the important issue is the "rate" of change. The C57 strain weight loss changed faster as dose varied compared to the other strains. (I realize it is hard to explain without the graphs, but check the reference to see for yourself. I focused on weight loss here, because the effect on RBC reduction was less pronounced.)

Anyway I found this to be an interesting paper, although I had an issue with one part of their conclusions. The authors note that host resistance leads to an evolutionary war with the pathogen, the "resistance" has a negative impact on the pathogen, in other words the pathogen can not grow as well. Thus, there is strong negative selective pressure, any pathogen cell that overcomes that resistance will take over very quickly (it will leave more descendants since it grows better). This effectively removes resistance, so the host is under strong negative selection to find new resistance mechanisms (and the circle of life continues). However, tolerance avoids this negative selective pressure, at least in the authors estimate. I find this to be extremely short-sighted. In the tolerant host there is still negative selection. The host may not be doing something specifically to prevent the pathogen's growth. However, there are finite resources. There are x number of RBC's the more one genotype of pathogen infects the more of that genotype that is passed on. So there is negative selection, by way of competition with your cousins (for one simple example). So now you have a host full of pathogens that are being "tolerated" but which are themselves evolving. Nothing spells accident waiting to happen in my mind than carrying around a lot of a pathogen all the while selecting for variants that may grow faster better stronger etc. So while I agree with the authors' assertion that the resistance counter-resistance cycle is ripe for continual selection for more pathogenic organisms (and resistant hosts I would add). The authors implicitly suggest that this isn't true in a tolerant model.

I wonder if this analogy is any good....I live in Minnesota and nature doesnt want me outside, thus it is currently butt ass cold. I resist that by putting on a jacket and hat when I go outside (suck it nature). Nature is less fit because Im out there stepping on it and being a nuisance, so over time it evolves to become 100°F hotter (-10°F to 90°F happens all the time, well every year). I am now much less fit, so I take off my jacket and mittens and put on shorts and a tank top (take that nature and people with discriminating tastes). And the cycle repeats. However, in my house nature is tolerant of me because Im not stepping on it and I walk around all year long in sweat pants (be happy Im wearing pants), I dont need a jacket or a tank top. Of course the furnace may break or the AC, there may (will) be a power outage, electric bills are too high so I cut back on heat and AC...crap where's that jacket/tank top. Damnit I had to evolve....well the hell with you nature, Im coming back outside and Im bringing my mountain bike!

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