Quantitative dose-response analysis untangles host bottlenecks to enteric infection

Host bottlenecks prevent many infections before the onset of disease by eliminating invading pathogens. By monitoring the diversity of a barcoded population of the diarrhea causing bacterium Citrobacter rodentium during colonization of its natural host, mice, we determine the number of cells that found the infection by establishing a replicative niche. In female mice the size of the pathogen's founding population scales with dose and is controlled by a severe yet slow-acting bottleneck. Reducing stomach acid or changing host genotype modestly relaxes the bottleneck without breaking the fractional relationship between dose and founders. In contrast, disrupting the microbiota causes the founding population to no longer scale with the size of the inoculum and allows the pathogen to infect at almost any dose, indicating that the microbiota creates the dominant bottleneck. Further, in the absence of competition with the microbiota, the diversity of the pathogen population slowly contracts as the population is overtaken by bacteria having lost the critical virulence island, the locus of enterocyte effacement (LEE). Collectively, our findings reveal that the mechanisms of protection by colonization bottlenecks are reflected in and can be generally defined by the impact of dose on the pathogen's founding population.