Quantitative dose-response analysis untangles host bottlenecks to enteric infection

Abstract

Host bottlenecks prevent many infections before the onset of disease by eliminating invading pathogens. Monitoring the diversity of a barcoded population of the diarrhea causing bacterium Citrobacter rodentium during colonization of its natural host, mice, allowed us to determine the number of cells that found the infection by establishing a replicative niche. The size of the pathogens founding population scaled with dose and was controlled by a severe yet slow-acting bottleneck. Reducing stomach acid or changing host genotype modestly relaxed the bottleneck without breaking the fractional relationship between dose and founders. In contrast, disrupting the microbiota caused the founding population to no longer scale with the size of the inoculum and allowed 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 contracted as the population was overtaken by bacteria that 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 pathogens founding population.