Investigating the Host-Pathogen Interaction: Tolerance in Perspective. Kyung Han Song, David Schneider. Dept of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA.

   Hosts can protect themselves from infections using two different mechanisms; The first is resistance, and it reduces microbe load. The second is tolerance, which helps the host to endure the damage caused by infection. Tolerance is measured by plotting the dose response curve of host health versus microbe load across a population. In practice, researchers have used two points (or sometimes only one point) to define tolerance curves and thus we know nothing about the shape these curves and have had to assume that they are straight. We plotted the full length of tolerance curves for a Drosophila infection and found that they have a useful shape that suggests new types of analyses. We use an infection model in which we challenged fruit flies with Listeria monocytogenes, which grows in the fly and produces a lethal outcome. These tolerance curves are best fit with a sigmoidal model. This lets us apply analyses used to study drug action and we can now monitor the slope of the curve (Hill coefficient) and the median inhibitory dose of bacteria (IC50) and the range of the response (both maximum and minimum health). We applied this model to a variety of mutant flies and bacteria. The tolerance curves for flies with resistance or tolerance phenotypes have very different shapes from each other. Bacterial virulence mutants showed shifts in the IC50 while the shape of the curve remained constant. This approach provides a more complete representation of host-pathogen interactions and lets us treat infections in a more quantitative manner.