Resistance versus tolerance: an evolutionary physiology approach

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A host can defend itself against an infection by directly reducing pathogen numbers, i.e., host resistance, or by reducing the harm that the infection does to its fitness, i.e., host tolerance. Given that resisting an infection can be costly for the host and result in autoimmune damage, it follows that a more resistant host is not necessarily fitter than a less resistant host. Tolerance is therefore an essential concept because it describes how well hosts are able to reduce the fitness costs of a given pathogen load. Resistance and tolerance are predicted to have contrasting effects on host-pathogen evolution and the spread of infectious diseases. It is therefore important to understand infection in the context of these two concepts, and we here propose to study them using an insect host, Drosophila melanogaster, and bacterial pathogens. Bacterial infections are dynamic processes. This means that host responses to pathogen replication and damage, and pathogen replication and counter-responses to the host, will change over time. In addition, it is becoming increasingly clear that bacterial infections can persist for the lifetime of an insect. This can be up to weeks or months in D. melanogaster, potentially increasing the opportunity and window for pathogen evolution. Both the dynamics and persistence of infection lead to the question of when during the infection, the host response, i.e., resistance or tolerance, should be captured, and how this affects our interpretation of host defences. In this project we propose to examine resistance and tolerance in the light of the dynamics and persistence of infection, through four complimentary objectives. We propose 1. To simultaneously examine the proteomic responses of hosts to persistent infections and the metabolic state of the persisting bacteria; 2. To identify where the bacteria are persisting inside their hosts; 3. To investigate the dynamics of fecundity tolerance in persistent infections, and the trade-off between fecundity- and mortality-tolerance, and 4. To examine what effects high and low resistance and fecundity tolerance have on host protein expression during persistent infections. The results from this project will provide novel insights into bacterial persistence, the host and pathogen responses during persistent infections, and resistance and tolerance along the trajectory of the infection process.