Benefits of immune protection versus immunopathology costs: A synthesis from cytokine KO models

The inflammatory response can produce damage to host tissues and in several infectious diseases the most severe symptoms are due to immunopathology rather than a direct effect of pathogen multiplication. One hypothesis for the persistence of inflammatory damage posits that the benefits of protection towards infection outweigh the costs. We used data on knocked-out (KO) cytokine models [and the corresponding wild-type (WT) controls] to test this hypothesis. We computed differences in pathogen load and host survival between WT and KO and divided them by the WT values. Using this ratio provides an internal control for variation in pathogen species, host strain, pathogen dose, and inoculation route. We predicted that i) if mortality is essentially due to immunopathology, there should be a loose association between pathogen load and host survival; ii) if mortality is essentially due to pathogen proliferation, we expect a tight association between pathogen load and host survival. The results provide strong support to this latter hypothesis. In 85% of WT -KO comparisons (n=126), an increase in pathogen load was associated with an increase in host mortality, and a decrease in pathogen load was associated with a decrease in host mortality. Overall, these findings are in agreement with the idea that immunopathology persists because immune protection confers immediate benefits in terms of infection clearance.